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Psychiatry Online

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Persons With Intellectual and Developmental Disabilities in the Mental Health System: Part 1. Clinical Considerations

  • Debra A. Pinals , M.D. ,
  • Lisa Hovermale , M.D. ,
  • Danna Mauch , Ph.D. ,
  • Lisa Anacker , M.D.

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Individuals with intellectual and developmental disabilities (IDD) are at high risk of co-occurring mental health conditions, including major depressive disorder, bipolar disorder, anxiety disorders, psychotic illnesses, impulse control disorders, and others. Because of symptoms associated with these illnesses and with the disabilities themselves, these individuals are often served in a mental health service system framework. However, treatment for them in these settings has typically not been sufficiently nimble, knowledgeable, or adept. Most mental health professionals receive little training about the needs of this population, and system structures typically bifurcate care, when, in reality, conditions can be complex and overlapping. In this first of two articles on care for persons with IDD in the mental health system, the authors provide a clinical overview of these neurodevelopmental disorders and of mental health and other conditions that co-occur with IDD. Considerations and challenges for treating this population in the mental health system include early recognition of mental health conditions, which often requires caregiver and family input, as well as information from a variety of additional collateral sources; the importance of trauma-informed and person-centered care; the promotion of self-determination through use of decision supports; use of approaches such as applied behavior analysis to develop a frame to address challenging behaviors; and the need to properly assess and provide thoughtful pharmacologic intervention when appropriate. The ability of individuals with IDD to thrive in a wide range of community integration opportunities depends on many factors, and clinicians must understand and use the available approaches for treating them.

People with intellectual and developmental disabilities (IDD) often have co-occurring mental health conditions.

Getting treatment for co-occurring IDD and mental health conditions typically requires accessing bifurcated care across two siloed care systems.

Even though the lack of integrated care options for individuals with IDD and mental health conditions and the need for a skilled workforce have long been recognized, system structural problems and professional training gaps persist.

Editor's Note: This article is part of a series based on the Technical Assistance Coalition working papers, which were originally written for NASMHPD and funded by SAMHSA. Matthew L. Goldman, M.D., M.S., is series coordinator and has helped curate these papers for publication in Psychiatric Services .

Persons with intellectual and developmental disabilities (IDD) often come to the attention of mental health services, including those in emergency and other crisis settings, inpatient psychiatric settings, and outpatient clinics, to name a few. This article is one of two originally conceptualized by the National Association of State Mental Health Program Directors on behalf of the Substance Abuse and Mental Health Services Administration. In this article, we describe diagnostic and treatment considerations for persons with IDD, including those pertaining to co-occurring mental illness. In the second article, we provide information related to systems and policy developments that can afford opportunities and present challenges in the delivery of care for persons with IDD ( 1 ).

Conceptualizing IDD: The Neurodevelopmental Disorders

Neurodevelopmental disorders are a category of disorders described in DSM-5 ( 2 ). This category includes a group of often co-occurring conditions, with onset in the developmental period—usually manifesting before a child enters primary school—and is characterized by deficits in “personal, social, academic, or occupational functioning” ( 2 ).

Included in this category are intellectual developmental disorder, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and other communication, motor, and learning disorders. Neurodevelopmental disorders are distinct from the neurocognitive disorders, which are characterized by a loss in cognitive functioning from a prior level (e.g., Alzheimer’s dementia) that may emerge at any age. Intellectual functioning may or may not be impaired in the neurodevelopmental disorders, and it is therefore important to understand the total abilities of the individual being served to best address his or her needs.

Intellectual Developmental Disorder

According to DSM-5 criteria for intellectual developmental disorder, an individual with this disorder needs to meet requirements in three areas: deficits in intellectual functioning, deficits in adaptive functioning, and onset of the deficits occurring in the developmental period ( 2 ). Although DSM-IV focused on IQ scores as a cornerstone of the definition, in DSM-5 the severity of the intellectual developmental disorder is classified as mild, moderate, severe, or profound based on adaptive functioning in conceptual, practical, and social domains, and the focus on IQ scores alone for diagnosis has been deemphasized ( 2 ).

The shift in thinking regarding an emphasis on adaptive functioning reflects studies indicating that IQ test scores, although helpful as an approximation of domains in functioning, are inadequate to capture the full picture of deficits and strengths that together make up an individual’s adaptive functioning ( 3 ). Related to current standards of focusing on strengths rather than deficits, the use of adaptive functioning provides a more comprehensive snapshot, without reliance on only a number or an IQ test score, which that can lead to stigmatization and labeling or even an underestimation of the individual’s capabilities ( Table 1 ).

TABLE 1. Examples of areas of difficulty in adaptive functioning domains among persons with intellectual and developmental disabilities

Conceptual skillsReading, writing, and language; telling time; handling money; executive functioning (planning, strategizing, and setting priorities); memory
Practical skillsActivities of daily living, such as bathing, toileting, and self-care; instrumental activities of daily living, such as telephone use, paying bills, grocery shopping, and transportation; skilled vocations; Legal decisions
Social skillsInterpersonal skills, social responsibility and cues, following rules, understanding risk (leading to decreased wariness or gullibility)

a Summarized from DSM-5 and American Association on Intellectual and Developmental Disabilities diagnostic information.

TABLE 1. Examples of areas of difficulty in adaptive functioning domains among persons with intellectual and developmental disabilities a

Intellectual developmental disorder, according to DSM-5, has an overall general population prevalence of approximately 1%, with the prevalence of severe intellectual disability estimated at 0.006% ( 2 , 4 ). Although estimates of the distribution of mild, moderate, severe, and profound intellectual developmental disorder vary in the literature, some estimate that of the population of persons with intellectual developmental disorder, 85% would be classified as having mild, 10% as having moderate, 4% as having severe, and 1%−2% as having profound intellectual developmental disorder ( 5 ). Although no consistent racial differences in the prevalence of intellectual developmental disorder have been noted, a gender difference appears to exist; studies have shown that males have a higher likelihood of being diagnosed as having both mild and severe intellectual developmental disorder ( 6 ).

Autism Spectrum Disorder

ASD is a neurodevelopmental disorder with onset in the early developmental period and is characterized by the presence of persistent deficits in social communication and social interaction in multiple contexts, as well as restricted and repetitive patterns of behavior, interests, or activities that cause clinically significant impairment in several areas of functioning, including personal, social, academic, or occupational ( 2 ).

As with intellectual developmental disorder, adaptive functioning is a key consideration with ASD. Some individuals with ASD exhibit marked deficits in socialization and communication that impair their ability to function adaptively, highlighting the possible discrepancy between cognitive capabilities that can be measured via IQ and level of support an individual requires ( 7 ). In screening for ASD, developmental screenings and comprehensive evaluations are often conducted. The American Academy of Pediatrics recommends that all children be screened for developmental delays and disabilities during regular well-child pediatrician visits at 9, 18, and 24 months ( 8 ).

According to DSM-5, in recent years the prevalence of ASD has been estimated at 1% of the population ( 2 ). Recent 2014 data from the Centers for Disease Control and Prevention (CDC) indicate that the prevalence may be as high as 1 in 59 children ( 9 ). No clear answer has yet been offered as to why ASD prevalence rates seem to be increasing; some point to changing ASD diagnostic criteria, and others postulate that higher rates reflect increased awareness and early identification of this disorder or underestimation of the prevalence in the past ( 10 , 11 ).

Other Neurodevelopmental Disorders

Although not the focus of this article, other neurodevelopmental disorders include ADHD and communication, motor, and specific learning disorders (i.e., those affecting math and reading.)

Co-occurring Conditions: Prevalence and Manifestations

Many conditions co-occur within the neurodevelopmental disorders, ranging widely in psychiatric, neurodevelopmental, and physical domains. In the mid-1900s, one school of thought generally subscribed to the idea that individuals with a developmental disability could not also have a mental illness and that any behavioral issues were instead a result of intellectual disability ( 12 ). However, research has shown the opposite to be true and has suggested that the prevalence of mental illness among persons with developmental disabilities is higher than in the general population ( 12 ). Psychiatric disorders have been shown to be three to four times higher among individuals with IDD, compared with the general population, and include illnesses such as major depressive disorder, bipolar disorders, psychotic disorders, anxiety disorders, impulse control disorders, major neurocognitive disorders, and stereotypic movement disorder ( 13 ).

Psychiatric disorders may manifest differently among individuals with intellectual developmental disorder, compared with the general population. The National Association for the Dually Diagnosed, in collaboration with the American Psychiatric Association, has greatly contributed to the field by compiling the Diagnostic Manual–Intellectual Disability , which suggests how psychiatric diagnosis can be adapted in working with people with IDD ( 14 ). Other neurodevelopmental disorders, such as ASD and ADHD, are also frequently comorbid with IDD ( 13 ). Although numerous studies show that ASD and IDD co-occur, the actual prevalence rates of IDD in ASD vary widely in the literature, ranging from 16.7% to 84% ( 15 ). Extreme individual variation in IQ has been noted among those with a diagnosis of ASD, requiring that sample size be quite large to achieve any approximation of accuracy. More recent studies may put the co-occurring prevalence rates around or below 50% ( 15 , 16 ). The close and often co-occurring relationship between IDD and ASD is also significant because individuals with IDD and ASD may have different needs and comorbidities, compared with individuals with IDD or ASD alone. Individuals with comorbid ASD and IDD may have higher rates of repetitive, restrictive, or self-injurious behaviors and may have a poorer prognosis ( 17 ). Awareness of the possibility of co-occurring psychiatric and neurodevelopmental disorders among individuals with IDD is important, because these co-occurring disorders may be targets for interventions that can affect behaviors, functioning, and outcome.

Traumatic brain injury (TBI) can also co-occur with IDD. Consequences of TBI can include impaired thinking, memory, and cognitive function; decreased hearing or vision; and even personality changes or emotional symptoms, such as depression, aggression, or impulse control issues ( 18 ).

In addition, it is helpful to be aware that sensory deficits (visual, tactile, auditory) are often undetected coexisting issues and that addressing such deficits can improve the quality of life of persons with IDD. Appropriate screening for and awareness of such deficits as possible added challenges can open windows to more effective treatment interventions.

More than 800 recognized syndromes listed in the Online Mendelian Inheritance in Man database ( ) are associated with intellectual disability, including the chromosomal abnormality trisomy 21, or Down syndrome, and the X-linked abnormality fragile X syndrome ( 19 ). Other genetic disorders associated with intellectual disability include but are not limited to Klinefelter syndrome, Williams syndrome, and tuberous sclerosis. Although these associations do exist, many regard genetic disorders as frequently associated with IDD, even though for most persons with IDD, no specific genetic abnormalities are found ( 19 ). Other nongenomic conditions associated with IDD can be due to preterm birth or perinatal in-utero exposures or teratogens (agents that affect the fetus), such as cigarette smoke or alcohol. Fetal alcohol syndrome (FAS) is a well-established condition that often results in developmental disability, and CDC studies have identified the prevalence of FAS as 0.2 to 1.5 for every 1,000 live births in certain areas of the United States ( 20 ).

Persons With IDD in the Mental Health System: Considerations and Challenges

Early recognition.

As noted above, one of the critical elements of working with individuals with IDD is to recognize that a person in services may have neurodevelopmental challenges and that adaptive functioning can vary among individuals. In identifying and working with persons with IDD, attending to the complexities of racial biases in how individuals may be recognized, diagnosed, supported, or treated is equally important. More work is also needed to understand how structural issues that lead to health disparities affect this population. Because there is tremendous heterogeneity within the IDD population, a cookie-cutter approach does not work well. Children in the mental health system with concomitant neurodevelopmental disorders should have a unique individualized educational plan (IEP) that addresses both mental health issues and IDD. Information about the IEP can inform practitioners who may be less familiar with a youth new to their services. Among adults and older adults who visit emergency services, who reside in nursing homes, or who present in any setting in the mental health system, individuals with IDD may not be the best source for providing their history of disorders and care. Gathering collateral information about them when they are in a care or support setting is important. Identifying whether the person has a guardian provides further information about the individual and the level of supports needed and can facilitate gaining proper consent from the guardian for particular treatments when needed.

Recognizing Trauma: Trauma-Informed Care, Supports, and Systems

It is especially important to consider the impact of trauma when caring for individuals with IDD. Research has indicated that individuals with IDD are more likely to be victimized and that children with moderate to severe intellectual disabilities are more likely to be neglected, sexually abused, emotionally abused, and physically abused, compared with children without such disabilities ( 21 ). In addition, children with speech or language disorders also appeared to be at increased risk of physical and emotional abuse, as well as neglect ( 21 ). Because of a potentially reduced capacity to process information, including traumatic memories, those with IDD may be at higher risk of developing posttraumatic stress disorder, compared with the general population ( 22 ). Complicating this picture further is research indicating that exposure to environmental stressors may also be higher in the IDD population. For instance, exposure to poverty is higher among individuals with intellectual disability, compared with their nondisabled peers, as is violence in the family and social isolation, which can also lead to decreased resilience in the face of other adverse life events and can compound the negative effects on an individual’s life ( 23 , 24 ). Negative life events were found to be significantly predictive of psychological trauma after 6 months in one study focusing specifically on individuals with intellectual disability ( 25 ).

For some persons with IDD, limited ability to communicate about traumatic experiences, as well as limited knowledge or social skills, may result in difficulty integrating their perception of traumatic events and their emotional response, which may result in affective aggression or behavioral dysregulation ( 26 ). In addition, there is often a perception that a person with IDD is not a reliable witness; one study found that jurors tend to perceive witness statements by a child with IDD as inherently unreliable ( 27 ). Ongoing victimization can result if an individual is not believed to be a reliable historian and his or her statements are not taken seriously. Specialized interviewing techniques for investigators are important to ensure the best assessment of victimization. Although challenging behavior in the IDD population is not uncommon, a subset of the externalizing behaviors may be a result of trauma ( 28 ).

Despite data showing higher rates of trauma among persons with IDD, there is still a lack of research on integration of trauma-informed care in organizations and systems providing support for the IDD population ( 29 ). At a systems level, to provide trauma-informed care means operating with the awareness of the pervasiveness of trauma as well as its impact.

Person-Centered Care, Self-Determination, and Decision-Making Supports

Person-centered care aims to shift from viewing individuals with IDD as persons with deficits and needs within a system to focusing on their strengths, capabilities, and potential to contribute to their community. Person-centered care aims to develop collaborative supports with individuals with IDD, focused on community presence and participation, positive relationships, respect, and competence ( 30 ). The concept of self-determination in the IDD population within this person-centered framework has been an area of significant focus in recent years. Self-determination is viewed by many as a fundamental human right—the right of an individual to manage his or her own life without unnecessary interference from others and to have more choice and control over life-affecting decisions ( 31 ). Individuals with IDD must have opportunities that enable them to exert control in their lives and to be self-advocates; having such opportunities is a strong predictor of self-determination ( 32 ). Studies investigating the impact of self-determination on individuals with IDD have found that those who were more self-determined or received more education on self-determination were more likely to be participatory and independent in performing community activities, more likely to have a higher quality of life, and more likely to be working for pay at higher hourly wages ( 33 – 36 ). Therefore, increased education on self-determination among individuals with IDD will continue to be important; such education includes but is not limited to decision making, problem solving, goal setting and attainment, self-advocacy, self-regulation, and self-awareness ( 37 ).

Issues of decision making are also important to consider for individuals with intellectual developmental disabilities, especially in a person-centered care construct. As a broad overview, generally adults are presumed competent to make their own decisions, unless a court of law finds them to be incompetent. If someone is found incompetent, a potential next step is guardianship, which is a legal process in which a court appoints an individual to make decisions in the best interests of the person who has been determined to lack capacity. Decisions made by guardians can include some or all decisions about health care, living arrangements, property, and other personal life decisions ( 38 ). Because guardianship is often considered to be the most restrictive option with the aim to protect a vulnerable person, other, less restrictive options prior to guardianship should also be considered—and considered first before moving toward guardianship. These include power of attorney, advance directives, special needs trust, or special bank accounts with cosigners ( 38 ).

Although guardianship is still used routinely, it is important to realize that some individuals question the idea of guardianship and the notion of a person’s being granted decision-making powers for someone else, and the effect it may have on the individual’s autonomy and independence ( 39 ). Recent disability research has moved toward an idea of supported decision making, which is a process in which instead of having an assigned guardian or substitute decision maker, an individual with IDD is supported by a circle of trusted others in making decisions for him- or herself, allowing the person to retain his or her right to make decisions ( 40 ). Supported decision making leaves the individual with IDD as the ultimate decision maker such that he or she is able to participate in society on an equal basis with others who make their own decisions ( 41 ). Those who help an individual with IDD with supported decision making may include peer supports, community services staff, personal ombudspersons, and personal assistants; good advance planning also has a role ( 42 ). Suggestions about how to more fully implement supported decision making include increasing education on decision-making skills, even in primary schools; providing more professional development; and educating families, judges, and the public on the abilities of individuals with IDD ( 43 ). In addition, providing an individual an opportunity to participate in the decision-making and planning process of transitioning from being a child with IDD to being an adult can also be important and should be focused on the individual’s preferences, needs, strengths, and desires ( 38 , 44 ).

Although advocates for supported decision making in lieu of legal guardianship are champions of this approach, some critics of supported decision making argue that more research is needed to delineate the similarities and differences between supported decision making and alternative surrogate decision makers before wide-scale, systemic changes are implemented ( 45 ). Either way, decisional capacity and deficits must be considered and addressed as individuals with IDD are seen in care systems.

Habilitative Treatment, Medications, and Other Supports

According to the Centers for Medicare and Medicaid Services, habilitative services are “Health care services that help a person keep, learn or improve skills and functioning for daily living” ( 46 ). After the Olmstead decision in 1999, most persons with IDD now live in the community. Federal waivers that provide support to persons with IDD living in the community require state assurances that the health and safety of these individuals are preserved through the ongoing provision of habilitative, medical, and support services. Federal waivers may provide for the housing needs of these individuals, or they may be supported in their own or family home. Habilitative services provided through waiver programs may include necessary staffing, supported employment, and assistance via coordination services. Additional habilitative services provided through federal waivers or state Medicaid plans may include physical and occupational therapy, speech-language pathology services, and other services for people with disabilities in various inpatient or outpatient settings ( 46 ). The supports described below are those most directly related to mental health care, but they do not reflect the total array of supports that may be needed or might be available.

Behavioral Supports

Behavioral supports are important at all stages of life, although some have suggested that individuals ages 16 to 22 have the greatest need for support, compared with the other age groups, suggesting that this period is an important area of focus ( 47 ). Among persons with IDD, challenging behavior can present for a multitude of biopsychosocial reasons, with functions including attention seeking, escape, access to tangible items, or automatic behaviors. Challenging behavior can present as aggression toward others or the environment, impulsivity, self-injury, or behaviors that are seen as socially unacceptable and may affect an individual’s adaptive functioning in the community. For example, an individual may engage in repetitive head banging to escape from an undesirable task or to seek attention. Although the data vary, some have estimated that the prevalence of behavior problems among persons with comorbid ASD and IDD is approximately 50% and that levels of severity of problem behavior can range from minor and time limited to severe, chronic, and potentially life threatening ( 48 , 49 ).

Provision of appropriate behavioral supports requires an analysis of the environments, the relationships, and the requirements placed on an individual. Given the prevalence of trauma in the lives of persons with IDD, the analysis should consider abuse, neglect, medical pain, or comorbidities, as well as irritation at staff turnover in the home. Behavioral supports include a variety of strategies that creatively avert challenging behaviors.

From a behavioral perspective, maladaptive or challenging behavior serves the purpose of getting a need met. All behavior, challenging or adaptive, can be construed as a learned behavior that has been historically reinforced by meeting a need or achieving a goal in some way. The task is to understand how challenging behaviors have been reinforced, perhaps inadvertently, and to change the reinforcement schedule to favor adaptive behaviors. Persons with IDD may have little pragmatic language or may lack the ability to communicate their needs. They may have receptive difficulty interpreting ordinary language, common idioms, social cues, tone of voice, facial expressions, or any other communication shortcuts. Again, regardless of verbal expressive abilities, what is said is less important that what is communicated in an array of nonverbal ways. Given these constraints, it is better to ask, “What does the behavior usually achieve?”

A biopsychosocial approach is an essential first step for the psychiatric clinician endeavoring to understand behavior and will be discussed in greater detail below; however, person-centered behavioral interventions would ideally occur prior to pharmacological intervention ( 50 ). Because systems now aim to prevent use of restraints, effective behavioral supports clarify the function of the behavior, are culturally appropriate, and are designed to meet the specific needs of the individual, with goals of removing environmental precipitants of challenging behaviors, emphasizing the idea of choice, and focusing on social integration ( 51 ).

Applied behavior analysis (ABA) is often linked to ASD, but the overarching principles involved in ABA are useful in intervening in all kinds of challenging behavior. Functional behavior assessment (FBA) is an umbrella term that consists of a variety of methods to hypothesize the function of a behavior. These include indirect measures, direct observation, and an experimental functional analysis method, which implies a strictly controlled experimental condition designed to understand the function of a challenging behavior by manipulating an independent variable. In FBA, an appropriately trained clinician observes the individual in multiple natural environments, interviews caretakers, and organizes data to reduce the challenging behavior. Shawler et al. ( 52 ) found that use of FBA to treat self-injury has dramatically increased since the 1990s and has continued to grow steadily.

Over the years, as the focus and literature base for identifying the function of behaviors has grown, additional models, such as those focused more on maximizing positive behaviors and incorporating the relationship with the individual, have been evolving, moving far away from the previously accepted use of aversive stimuli ( 53 ). Both ABA and positive behavior support approaches examine behavior and help the individual function more optimally in his or her environment. Positive behavior interventions and supports, used in school systems originally, has been extended to the IDD population and the population of persons with serious mental illness in state hospitals and other parts of the mental health continuum of care.

A review of more than 100 studies involving young people with co-occurring ASD and IDD and challenging behaviors found that behavioral interventions, such as those described above, resulted in more than 86% of individuals benefiting from treatment; 65% were characterized as “responders,” whose problem behavior was reduced by more than 80% ( 48 ). In addition, use of behavioral intervention strategies with a consequence-based structure and clear limits (i.e., withdrawal of privileges), along with reinforcement of positive behaviors as described above, is often recommended ( 50 ). Mental health professionals should work with individuals with appropriate training in FBA to achieve the best possible gains for individuals being served.

Pharmacologic and Nonpharmacologic Therapeutic Supports

Appropriate and effective pharmacologic supports depend on accurate and detailed assessments leading to plausible diagnostic hypotheses. The biopsychosocial model can facilitate this approach. During the first psychiatric encounter in an emergency, urgent, or nonacute setting, a critical task is to get an understanding of the baseline of the person with IDD. Subsequent clinical inquiry emphasizes psychosocial changes, symptoms or behavioral changes indicative of medical issues, trademark behaviors and their function, history of trauma, and, finally, any evidence that may support the assignment of a diagnosis of a mental or substance use disorder.

The impact of psychosocial stressors tends to be underestimated in this population. The effects of changing group living environments, changing staff, lack of access to family, seeing siblings achieve adult milestones, and losing parents to death and old age tend to be minimized. There is a definite role for psychotherapy in understanding the emotional response of the person with IDD and assisting the person to process events and his or her responses. Any diagnostic hypothesis has to be put in context. Knowing if the person has reacted to a similar stressor in an equivalent way in the past builds an understanding of his or her behavioral function.

Medical conditions can also be overlooked among individuals who are not well equipped to localize pain, describe symptoms, or assist the clinician in other ways to identify a somatic condition. Behavior to achieve a function is discussed above. For some individuals, aggression and property destruction or disruption, as well as self-injurious behavior, might be a method of expressing pain or distress from a medical condition. Empirical data on this linkage are lacking, yet impacted wisdom teeth, migraine headaches, severe premenstrual syndrome, peptic ulcer disease, and gastroesophageal reflux disease are all common medical conditions that can be very painful or distressing and that do not manifest outwardly, even to observant treatment providers. Suspicion of painful conditions should be followed up with proper medical attention.

Gaining a sense of the usual temperament and personality style of the person with IDD helps to filter possibilities. Trauma and its impact on personality and temperament are more challenging to identify and address in this group, compared with more neurotypical individuals, and often confound pharmacologic treatments. Arriving at a psychiatric diagnosis also depends greatly on accurate data transfer from the home environment. Data about sleep, weight changes, or shifts in appetite can be helpful clues indicating psychiatric illness, if these data have not been obscured by other pharmacologic interventions.

A major departure from an individual’s baseline, which cannot be convincingly attributed to other factors, may at least warrant an empiric trial of a psychotropic agent expected to address the identified symptoms. This is best done with the support of a behavioral plan developed after careful analysis (described above) and with a review of data on behavioral targets that the clinician anticipates will be affected by the medication. Most often these targets are physical aggression, property destruction or disruption, verbal aggression or disruption, elopement, and sexually inappropriate behavior. All these behaviors tend to arouse strong emotions among caretakers, highlighting why it is important to have data rather than anecdotal report. No clinician should prescribe medications as part of a long-term treatment plan to simply and solely suppress undesired behavior.

If medications are ultimately deemed appropriate, they are best initiated by conducting empiric trials, using data-driven feedback. It is critical for the prescriber to maintain an open mind that allows constant reassessment of information at hand. Strong collaboration should be practiced between clinical team members, including psychiatrists, direct support professionals, clinicians, family, and the person in treatment, so that treatment is person centered. Medications can be associated with significant risk and adverse outcomes. Persons with IDD should not be unnecessarily exposed to these risks, especially because the evidence base for psychopharmacology in this population is limited.

An important consideration is the risk of polypharmacy, which may lead to complex drug-drug interactions and erosion of the individual’s quality of life. Although the quality and quantity of research on this subject are limited, low-dose antipsychotics, such as risperidone, are the most commonly used pharmacologic intervention, followed by antidepressants and mood stabilizers ( 54 ). Many medications investigated in studies on this topic are being used off-label—that is, not for the indication approved by the Food and Drug Administration ( 55 ). The National Core Indicators published a report in 2012 examining use of medications in public IDD systems ( 56 ). The final data set included 8,390 adults, and the study found that 53% of them were taking medication to address one of three mental health conditions (mood, anxiety, or psychosis) or behavioral challenges—or a combination of those issues. Given the complexity of prescribing medications for this population, whether those medications were actually indicated is difficult to know. This difficulty highlights the challenge of prescribing medications in this population—namely, the risk of undertreating an actual, comorbid psychiatric disorder versus inappropriately medicating a behavioral issue.


Large intermediate care facilities and long-term wards of state psychiatric hospitals are no longer the mainstay of services for persons with IDD. The ability of individuals with IDD to thrive in a wide range of community integration opportunities depends on their optimal behavioral and somatic health, and clinicians must understand and use the available approaches for treating them. Individuals with IDD in the mental health system have unique needs, and attention to their co-occurring psychiatric and IDD conditions is critical. The mental health system presents many challenges in working effectively with persons with IDD, but with increased attention to this population’s varied and individualized needs, clinical treatment approaches can be improved in provider organizations and across care systems.

This work was presented at the annual meeting of the American Psychiatric Association, New York City, May 5–9, 2018.

Development of this work was partially supported by a contract from the Substance Abuse and Mental Health Services Administration (SAMHSA) to the National Association of State Mental Health Program Directors.

The views, opinions, and content expressed do not necessarily reflect the views, opinions, or policies of the Center for Mental Health Services, SAMHSA, the U.S. Department of Health and Human Services, or any state or other institutions with which the authors are affiliated.

The authors report no financial relationships with commercial interests.

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  • Elizabeth M. Stone , Ph.D., M.S.P.H. ,
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  • Content and Other Resources Recommendations for Individuals with Intellectual Disability: A Review 26 October 2022 | Electronics, Vol. 11, No. 21
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  • Yaara Zisman-Ilani , Ph.D., M.A.

research on intellectual disabilities (mental retardation) indicates that

  • Mental illness and mental retardation
  • Patient needs
  • Mental illness and intellectual disability
  • Intellectual disability disorder

research on intellectual disabilities (mental retardation) indicates that

  • Intellectual Disability
  • Author: Ari S Zeldin, MD, FAAP, FAAN; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA  more...
  • Sections Intellectual Disability
  • Practice Essentials
  • Pathophysiology
  • Mortality/Morbidity
  • Laboratory Studies
  • Imaging Studies
  • Other Tests
  • Histologic Findings
  • Approach Considerations
  • Medical Care
  • Consultations
  • Long-Term Monitoring
  • Medication Summary
  • CNS stimulants
  • Alpha-adrenergic agonists
  • Neuroleptic drugs (antipsychotics)

Intellectual disability (ID), is a descriptive term for subaverage intelligence and impaired adaptive functioning arising in the developmental period (< 18 years).

Signs and symptoms

Patients with ID and developmental delays may demonstrate the following:

Language delay: One of the first signs of ID may be language delays, including delays in expressive language (speech) and receptive language (understanding)

Fine motor/adaptive delay: Significant delays in activities such as self-feeding, toileting, and dressing are typically reported in children with ID

Cognitive delay: Difficulties with memory, problem-solving, and logical reasoning

Social delays: Lack of interest in age-appropriate toys and delays in imaginative play and reciprocal play with age-matched peers

Gross motor developmental delays: Infrequently accompany the cognitive, language, and fine motor/adaptive delays associated with ID unless the underlying condition results in both ID and cerebral palsy.

Behavioral disturbances: Infants and toddlers may be more likely to have difficult temperaments, hyperactivity, disordered sleep, and colic; associated behaviors may include aggression, self-injury, defiance, inattention, hyperactivity, sleep disturbances, and stereotypic behaviors.

Neurologic and physical abnormalities: Prevalence of ID is increased among children with seizure disorders, microcephaly, macrocephaly, history of intrauterine or postnatal growth retardation, prematurity, and congenital anomalies

Evaluation of patients for ID can include the following examinations:

Head circumference: Microcephaly correlates highly with cognitive deficits; macrocephaly may indicate hydrocephalus, is associated with some inborn errors of metabolism, and may be seen early on in some children later diagnosed with autism [ 1 , 2 ]

Height: Short stature may suggest a genetic disorder, fetal alcohol syndrome, or hypothyroidism; tall stature may suggest fragile X syndrome (FraX), Soto syndrome, or some other overgrowth syndrome associated with ID

Neurologic: This examination should include assessments of head growth (for microcephaly/macrocephaly), muscle tone (for hypotonia or spasticity), strength and coordination, deep tendon reflexes, persistent primitive reflexes, ataxia, and other abnormal movements, such as dystonia or athetosis.

Sensory: Children with disabilities and ID are more likely than other children to have visual impairment and hearing deficits

Skin: Findings can include hyperpigmented and hypopigmented macules, such as café-au-lait macules (associated with neurofibromatosis type 1), as well as ash-leaf spots (associated with tuberous sclerosis), fibromas, and irregular pigmentation patterns

Extremities: Although ID with multiple congenital anomalies and major malformations accounts for only 5-10% of all cases, most of these affected individuals have 3-4 minor anomalies, especially involving the face and digits

See Clinical Presentation for more detail.

Laboratory studies

Array-based comparative genetic hybridization (CGH), or microarray

High-resolution karyotype

Fragile X testing

FISH probes

Next-generation sequencing through panels and/or whole exomes

Imaging studies

Brain magnetic resonance imaging (MRI): Should be conducted in any child with global developmental delays or ID [ 3 ]

Head computed tomography (CT) scanning: Preferred imaging study for calcifications that may be identified with TORCH infections (ie, toxoplasmosis, other infections, rubella, cytomegalovirus [CMV], herpes simplex) or when tuberous sclerosis is suspected or craniosynostosis is a concern

Skeletal films: Assist with phenotypic description, syndrome characterization, and assessment of growth

Additional tests

Detailed assessment by a licensed professional is necessary to confirm the diagnosis of ID. Some of the most commonly used tests in children include the following:

Bayley Scales of Infant Development

Stanford-Binet Intelligence Scale

Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R)

Wechsler Intelligence Scale for Children–IV (WISC-IV)

Vineland Adaptive Behavior Scales-II

See Workup for more detail.

The mainstay of ID treatment is the development of a comprehensive management plan for the condition. The complex habilitation plan for the individual requires input from care providers from multiple disciplines, including special educators, language therapists, behavioral therapists, occupational therapists, and community services that provide social support and respite care for families affected by ID.

Neuropathic pain due to dysautonomia or motor spasms may create chronic disturbances. Treatment should be prompt and include the following:

Nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for mild pain

Tramadol or equivalent for moderate pain

Opioids for severe pain as indicated

Management of sources of pain

No specific pharmacologic treatment is available for cognitive impairment in the developing child or adult with ID. [ 4 ] Medications, when prescribed, are targeted to specific comorbid psychiatric disease or behavioral disturbances.

The psychostimulant class of drugs is commonly prescribed in individuals with ID, because of the diagnosis of attention deficit with or without hyperactivity disorder (ADHD/ADD) in 6-80% of these patients. However, few studies on stimulants in people with ID are available. The studies that do exist indicate that benefits vary, and significant adverse events, such as severe social withdrawal, increased crying, drowsiness, and irritability, have been noted, especially at higher doses of methylphenidate (0.6 mg/kg). [ 5 ]

The neuroleptic drugs are the most frequently prescribed agents for targeting behaviors such as aggression, self-injury, and hyperactivity in people with ID. These indications are generally off-label for ID and caution is advised.

See Treatment and Medication for more detail.

Intellectual disability (ID) is a descriptive term for subaverage intelligence and impaired adaptive functioning arising in the developmental period (< 18 y). ID and other neurodevelopmental disabilities are seen often in a general pediatric practice.

The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5) , characterizes ID by deficits in general mental abilities, such as reasoning, problem solving, planning, abstract thinking, judgment, academic learning, and learning from experience. The deficits result in impairments to adaptive functioning, such that the individual fails to meet standards of personal independence and social responsibility in one or more aspects of daily life, including communication, social participation, academic or occupational functioning and personal independence at home or in community settings. [ 6 ]

Approximately 10% of children have some learning impairment, while as many as 3% manifest some degree of ID. The population prevalence of these combined disorders of learning rivals that of the common childhood disorder asthma.

ID originates during the developmental period (i.e., conception through age 18 years). ID is categorized as a neurodevelopmental disorder and is distinct from the neurocognitive disorders, which are characterized by a loss in cognitive functioning. Major neurocognitive disorder may occur with ID such as when an individual with Down syndrome develops Alzheimer's disease, for example. In a case like this, both ID and neurocognitive disorder would be diagnosed.

ID also can be categorized as syndromic, if associated with dysmorphic features, or nonsyndromic, if not associated with dysmorphisms or malformations. The understanding of specific ID syndromes is expanding with recent molecular genetic advances. More than 800 recognized syndromes listed in the Online Mendelian Inheritance in Man (OMIM) database are associated with ID, reflecting clinical diagnostic advances in the field. The most common associated chromosomal abnormality is trisomy 21, or Down syndrome . The most common X-linked abnormality associated with ID is fragile X syndrome . However, for most cases of ID, no specific genetic abnormalities are found.

Some forms of ID are due to nongenetic factors and may be identifiable by their associated dysmorphisms and clinical presentation. Examples include prenatal exposure to teratogens (e.g., anticonvulsants, warfarin, alcohol) or prenatal thyroid dysfunction. Prenatal and postnatal exposure to lead and the associated decrement in IQ may increase an individual's chance of functioning in the ID range. ID may result from an acquired infection or injury during the developmental period from, for example, a severe head injury or meningitis or encephalitis infection

Diagnostic criteria (DSM-5)

Intellectual disability (intellectual developmental disorder) is a disorder with onset during the developmental period that includes both intellectual and adaptive functioning deficits in conceptual, social and practical domains. According to the DSM-5 , the following three criteria must be met: [ 6 ]

Deficits in intellectual functions, such as reasoning, problem solving, planning, abstract thinking, judgment, academic learning, and learning from experience, confirmed by both clinical assessment and individualized, standardized intelligence testing.

Deficits in adaptive function that results in failure to meet developmental and sociocultural standards for personal independence and social responsibility. Without ongoing support, the adaptive deficits limit functioning in one or more activities of daily life, such as communication, social participation, and independent living, across multiple environments, such as home, school, work, and community.

Onset of intellectual and adaptive deficits during the developmental period.

Severity is specified as mild, moderate, severe, or profound based on the level of impairment in adaptive functioning, and not IQ scores, because it is adaptive functioning that determines the level of support required. The three domains of adaptive functioning are conceptual, social, and practical.

In addition to severity, the specifier “associated with a known medical or genetic condition or environmental factor” may be given. Examples include genetic disorders, such as fragile X syndrome, tuberous sclerosis, and Rett syndrome; and environmental factors including fetal alcohol exposure (even in the absence of fetal alcohol syndrome).

Intellectual disability (ID) is the end result of many disorders of CNS function. Most individuals with significant intellectual impairment have no discernible structural abnormalities of the brain. CNS malformations, a visual correlate of the disorders, are diagnosed in 10-15% of cases; dysfunction is localized primarily to the cortical structures, including the hippocampus and the medial temporal cortex. The most common malformations consist of neural tube defects, hydranencephaly, and microcephaly. Less commonly, CNS malformations include disorders of migration (the lissencephalies) and agenesis of the corpus callosum.

Multiple congenital anomaly syndromes with malformations confined to nonneurologic organ systems may be present in 5% of all patients with ID. Between 3% and 7% of cases may be associated with a wide array of inborn errors of metabolism complicated by multiorgan system disease. Alcohol exposure in utero may account for as many as 8% of those with mild ID.

Most individuals with mild ID and other learning disorders do not have other neurologic complications, CNS malformations, or dysmorphisms. They are more likely, however, to be born into families of low socioeconomic status, low IQ, and little education. The etiologic contribution of poverty to their poor cognitive function remains unclear. Clearly, however, poor cognitive functioning and ID are correlated positively with a life of poverty.

United States

The frequency of intellectual disability (ID) of all degrees ranges from 1% to 3% of the population. ID has an overall general population prevalence of approximately 1% and prevalence rates vary by age. Prevalence for severe intellectual disability is approximately 6 per 1,000. [ 6 ]


A study with excellent ascertainment conducted in Aberdeen, Scotland, yielded a prevalence of 1 in 300 for severe ID and 1 in 77 for mild ID. Among those with severe ID were more boys than girls (male-to-female ratio 1.2:1), and among those with IQ > 70, in the mild range of deficiency, boys exceeded girls by a ratio of 2.2:1. [ 7 ]

Although prevalence rates vary from country to country, the variance in prevalence may be attributed to ascertainment bias, the standardization methods employed from study to study, and a generalized upward drift in IQ scores over time. Even so, the greatest variance in statistics of prevalence is most likely to fall within the category of mild ID, a group for which the ascertainment bias is large.

Race-, sex-, and age-related differences in incidence

Consistent racial differences in prevalence of ID and associated mortality rates are not known to exist.

The gender ratios for mortality and morbidity do not differ from the gender ratio noted in the severe/profound ranges of intellectual disability (ie, male-to-female ratio, 1.2:1).

ID refers to intellectual impairment that develops prior to the age of 18 years.

Certain syndromes associated with ID, such as Down syndrome, are associated with shorter life expectancy than the general population. In a comparison of those with ID with and without Down syndrome from the California Department of Developmental Services cohort, excess mortality in the Down syndrome group tended to decrease with advancing age up to 35-39 years but increased thereafter. The increase in death rate from age 40 years was steeper in patients with Down syndrome than in those without Down syndrome. [ 8 ]

Intellectual disability (ID) itself is not necessarily associated with an increased premature death rate. However, individuals with severe to profound ID experience a decreased life expectancy related to the underlying etiology or additional complicating neurologic disorders, such as epilepsy. Neurologic dysfunction resulting in immobility, significant oral motor incoordination, dysphagia, and aspiration confers a greater risk of premature death than ID itself. When significant neurologic dysfunction is associated with other organ system anomalies, an individual's life expectancy is shortened further.

Respiratory disease is the most prevalent cause of death among individuals with profound ID. In particular, respiratory infections were the leading cause of death among a Finnish cohort of children with ID. [ 9 ] For those affected by mild ID, life expectancy does not differ from that of the general population.

Comorbid psychiatric conditions are diagnosed more frequently in those with intellectual disabilities than in the general population. Even so, psychiatric disorders probably are underappreciated in this population.

Attention deficit/hyperactivity disorder (ADHD) is diagnosed in 8-15% of children and 17-52% of adults with ID.

Self-injurious behaviors require treatment in 3-15%, particularly in the severe range of ID.

Major depression, bipolar disorders, anxiety disorders, and other mood disorders are the most common psychiatric diagnoses in adults with ID. Obsessive-compulsive disorder, conduct disorder, tic disorders, and other stereotypic behaviors are also diagnosed more commonly in those with ID. Schizophrenia may have a prevalence of 3% in individuals with ID, compared to 0.8% in the general population.

In the 1970 Isle of Wight study, as many as 30% of children with ID exhibited an emotional or behavioral disorder, compared to 6% of children in the general population. ID compounded by epilepsy conferred a 56% risk of comorbid psychiatric disease in this study. [ 10 ]

Occult visual and auditory deficits occur in 50% of those with ID, particularly when refractive errors are considered.

The rates of transmittable diseases, including sexually transmitted diseases (STDs), hepatitis B, and Helicobacter pylori infection, are increased significantly among individuals with ID.

One in 5 individuals with ID also has cerebral palsy (CP).

As many as 20% of individuals with ID have seizures.

GI complications with ID include feeding dysfunction, excess drooling, reflux esophagitis, and constipation.

GU complications with ID include urinary incontinence and poor menstrual hygiene.

A profound social morbidity affects individuals with ID and their families. This morbidity can be measured in lost wages, dependence on social services, impaired long-term relationships, and emotional suffering.

Individuals with a diagnosis of intellectual disability with co-occurring mental disorders are at risk for suicide. Screening for suicidal thoughts is essential in the assessment process.

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Ellis JM, Tan HK, Gilbert RE, Muller DP, Henley W, Moy R, et al. Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial. BMJ . 2008 Mar 15. 336(7644):594-7. [QxMD MEDLINE Link] . [Full Text] .

[Guideline] Moeschler JB, Shevell M. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics . 2006 Jun. 117(6):2304-16. [QxMD MEDLINE Link] . [Full Text] .

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Developmental surveillance and screening of infants and young children. Pediatrics . 2001 Jul. 108(1):192-6. [QxMD MEDLINE Link] .

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Mao R, Wang X, Spitznagel EL. Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart. Genome Biol . 2005. 6(13):R107. [QxMD MEDLINE Link] . [Full Text] .

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Schroeder S, Gerry M, Gertz G, Velasquez F. Final Project Report: Usage of the Term "Mental Retardation:" Language, Image and Public Education. June 2002.

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Contributor Information and Disclosures

Ari S Zeldin, MD, FAAP, FAAN Staff Pediatric Neurologist, Naval Medical Center San Diego Ari S Zeldin, MD, FAAP, FAAN is a member of the following medical societies: American Academy of Neurology , American Academy of Pediatrics , Child Neurology Society Disclosure: Nothing to disclose.

Alicia T F Bazzano, MD, PhD, MPH Clinical Faculty, Division of Pediatric Emergency Medicine, Harbor/UCLA Medical Center; Chief Physician, Westside Regional Center Alicia T F Bazzano, MD, PhD, MPH is a member of the following medical societies: Alpha Omega Alpha , American Academy of Pediatrics , American Public Health Association , American Society for Bioethics and Humanities Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Received salary from Medscape for employment. for: Medscape.

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Medical Director, Tulane Center for Autism and Related Disorders, Tulane University School of Medicine; Pediatric Neurologist and Epileptologist, Ochsner Hospital for Children; Professor of Neurology, Louisiana State University School of Medicine Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine , American Academy of Neurology , American Academy of Pediatrics , American Epilepsy Society , American Medical Association , American Neurological Association , The Society of Federal Health Professionals (AMSUS) , Child Neurology Society , Southern Pediatric Neurology Society Disclosure: Nothing to disclose.

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Karen H Harum, MD to the development and writing of this article.

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Intellectual Disability

  • Symptoms and Signs |
  • Diagnosis |
  • Treatment |
  • Prognosis |
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Intellectual disability is characterized by significantly subaverage intellectual functioning (often expressed as an intelligence quotient 70 to 75) combined with limitations of adaptive functioning (ie, communication, self-direction, social skills, self-care, use of community resources, and maintenance of personal safety), along with demonstrated need for support. Management consists of education, family counseling, and social support.

Intellectual disability is considered a neurodevelopmental disorder. Neurodevelopmental disorders are neurologically based conditions that appear early in childhood, typically before school entry, and impair development of personal, social, academic, and/or occupational functioning. They typically involve difficulties with the acquisition, retention, or application of specific skills or sets of information. Neurodevelopmental disorders may involve dysfunction in one or more of the following: attention, memory, perception, language, problem-solving, or social interaction. Other common neurodevelopmental disorders include attention-deficit/hyperactivity disorder , autism spectrum disorder , and learning disorders (eg, dyslexia ).

Intellectual disability must involve childhood onset of deficits in both of the following:

Intellectual functioning (eg, in reasoning, planning and problem solving, abstract thinking, learning at school or from experience)

Adaptive functioning (ie, ability to meet age- and socioculturally appropriate standards for independent functioning in activities of daily life)

Basing severity on IQ alone (eg, mild, 52 to 70 or 75; moderate, 36 to 51; severe, 20 to 35; and profound, < 20) is inadequate. Classification must also account for the level of support needed ( 1 ):

Intermittent: Occasional support needed

Limited: Support such as a day program in a sheltered workshop

Extensive: Daily, ongoing support

Pervasive: High level of support for all activities of daily living, possibly including extensive nursing care

Such an approach focuses on a person’s strengths and needs, relating them to the demands of the person’s environment and the expectations and attitudes of the family and community.

Approximately 3% of the population functions at an IQ of < 70, which is at least 2 standard deviations below the mean IQ of the general population (IQ of 100); if the need for support is considered, only approximately 1% of the population has severe intellectual disability ( 1 ).

Severe intellectual disability occurs in families from all socioeconomic groups and educational levels. Performance on intelligence and achievement tests is affected by socioeconomic status. Nevertheless, studies suggest that genetic factors play roles even in milder cognitive disabilities ( 2 ).

General references

1. Schalock RL, Luckasson R, Tassé MJ : An Overview of Intellectual Disability: Definition, Diagnosis, Classification, and Systems of Supports (12th ed.).  Am J Intellect Dev Disabil 126(6):439–442, 2021. doi:10.1352/1944-7558-126.6.439

2. Ilyas M, Mir A, Efthymiou S, Houlden H : The genetics of intellectual disability: advancing technology and gene editing.  F1000Res 9:F1000 Faculty Rev-22, 2020. doi:10.12688/f1000research.16315.1

Etiology of Intellectual Disability

Intelligence is both genetically and environmentally determined. Children born to parents with intellectual disability are at increased risk of a range of developmental disabilities, but clear genetic transmission of intellectual disability is unusual. Although chromosomal microarray analysis and whole genome sequencing of the coding regions (exome) have increased the likelihood of identifying some causes of intellectual disability, a cause of intellectual disability in a specific person often cannot be identified. A cause is most likely to be identified in severe cases. Deficits in language and personal–social skills also may be due to emotional problems, environmental deprivation, learning disorders , or deafness rather than intellectual disability.

Prenatal factors

A number of chromosomal anomalies and genetic, metabolic, and neurologic disorders can cause intellectual disability (see table Some Chromosomal and Genetic Causes of Intellectual Disability ).

Congenital infections that can cause intellectual disability include rubella and those due to cytomegalovirus , Toxoplasma gondii , Treponema pallidum , herpes simplex virus , or HIV . Prenatal Zika virus infection may cause congenital microcephaly and associated severe intellectual disability.

Prenatal medication and toxin exposure can cause intellectual disability. Fetal alcohol syndrome

Severe undernutrition during pregnancy may affect fetal brain development, resulting in intellectual disability.

Perinatal factors

Complications related to prematurity , central nervous system bleeding , periventricular leukomalacia, breech or high forceps delivery, a multifetal pregnancy , placenta previa , preeclampsia , and perinatal asphyxia may increase the risk of intellectual disability. The risk is increased in small-for-gestational-age infants ; intellectual impairment and decreased weight share similar causes. Very low- and extremely low-birth-weight infants have variably increased chances of having intellectual disability, depending on gestational age, perinatal events, and quality of care.

Postnatal factors

Undernutrition and environmental deprivation (lack of physical, emotional, and cognitive support required for growth, development, and social adaptation) during infancy and early childhood may be the most common causes of intellectual disability worldwide. Viral and bacterial encephalitides (including HIV-associated neuroencephalopathy) and meningitides (eg, pneumococcal infections , Haemophilus influenzae infection ), poisoning (eg, lead , mercury), and accidents that cause severe head injuries or asphyxia may result in intellectual disability.

Symptoms and Signs of Intellectual Disability

The primary manifestations of intellectual disability are

Slowed acquisition of new knowledge and skills

Immature behavior

Limited self-care skills

Some children with mild intellectual disability may not develop recognizable symptoms until preschool age. However, early identification is common among children with moderate to severe intellectual disability and among children in whom intellectual disability is accompanied by physical abnormalities or signs of a condition (eg, cerebral palsy ) that may be associated with a particular cause of intellectual disability (eg, perinatal asphyxia). Delayed development is usually apparent by preschool age, often manifesting more as delay in communication than in motor skills. Among older children, hallmark features are a low IQ combined with limitations in adaptive behavior skills (eg, communication, self-direction, social skills, self-care, use of community resources, maintenance of personal safety). Although developmental patterns may vary, it is much more common for children with intellectual disability to experience slow progress than developmental arrest.

Behavioral problems are the reason for most psychiatric referrals and out-of-home placements for people with intellectual disability. Behavioral problems are often situational, and precipitating factors can usually be identified. Factors that predispose to unacceptable behavior include

Lack of training in socially responsible behavior

Inconsistent limit setting

Reinforcement of faulty behavior

Impaired ability to communicate

Discomfort due to coexisting physical problems and mental health disorders such as depression or anxiety

In institutional settings (now uncommon in the United States), overcrowding, understaffing, and lack of activities contribute to both behavior challenges and to limited functional progress. Avoidance of long-term placement in large congregate care settings is extremely important in maximizing the individual's success.

Comorbid disorders

Comorbid disorders are common, particularly attention-deficit/hyperactivity disorder , mood disorders ( depression , bipolar disorder ), autism spectrum disorder , anxiety disorder , and others.

Some children have comorbid motor or sensory impairments, such as cerebral palsy or other motor deficits, language delays, or hearing loss. Such motor or sensory impairments can mimic cognitive impairment but are not in themselves causes of it. As children mature, some develop anxiety or depression if they are socially rejected by other children or if they are disturbed by the realization that others see them as different and deficient. Well-managed, inclusive school programs can help maximize social integration, thereby minimizing such emotional responses.

Diagnosis of Intellectual Disability

Prenatal testing, intelligence and developmental assessment.

Imaging of the central nervous system

Genetic testing

Prenatal testing can be done to determine whether the fetus has abnormalities, including genetic disorders, that predispose to intellectual disability.

From birth on, growth and development , including cognitive ability, are routinely assessed at well-child visits. For suspected cases of intellectual disability, development and intelligence are assessed in greater detail, typically by early intervention or school staff.

Establishing intellectual disability is followed by efforts to determine a cause, often including central nervous system (CNS) imaging and genetic and metabolic testing. Accurate determination of the cause may provide a developmental prognosis, suggest plans for educational and training programs, help in genetic counseling, and relieve parental guilt.

Genetic counseling may help high-risk couples understand possible risks. If a child has intellectual disability, evaluation of the etiology can provide the family with appropriate risk information for future pregnancies.

Prenatal testing may be done in high-risk couples who choose to have children. Prenatal testing enables couples to consider pregnancy termination and subsequent family planning. Testing includes

Amniocentesis or chorionic villus sampling

Quad screen


Maternal serum alpha-fetoprotein

Noninvasive prenatal screening

Amniocentesis or chorionic villus sampling may detect inherited metabolic and chromosomal disorders, carrier states, and CNS malformations (eg, neural tube defects, anencephaly) and may be offered to pregnant patients, especially those > 35 years of age, to detect Down syndrome or an inherited metabolic disorder.

The quad screen (ie, measurement of maternal levels of beta- human chorionic gonadotropin  [beta-hCG], unconjugated estriol, alpha-fetoprotein, and inhibin A) is recommended for most pregnant patients to evaluate risk of Down syndrome, trisomy 18, spina bifida, and abdominal wall defects.

Ultrasonography may also identify CNS defects.

Maternal serum alpha-fetoprotein is a helpful screen for neural tube defects, Down syndrome, and other abnormalities.

Noninvasive prenatal screening (NIPS) methods can be used to identify numerical chromosome abnormalities and have been used to identify some larger microdeletion syndromes such as 22q11 deletion.

Standardized intelligence tests can measure subaverage intellectual ability but are subject to error, and results should be questioned when they do not match clinical findings; illness, motor or sensory impairments, language barriers, and/or socioeconomic status may hamper a child’s test performance. Such tests also have a middle-class bias but are generally reasonable in appraising intellectual ability in children, particularly in older ones.

Developmental screening tests such as the Ages and Stages Questionnaire (ASQ) or the Parents’ Evaluation of Developmental Status (PEDS) provide gross assessments of development for young children and can be given by a physician or others. Such measures should be used only for screening and not as substitutes for standardized intelligence tests, which should be given by qualified psychologists. A neurodevelopmental assessment should be initiated as soon as developmental delays are suspected.

A developmental pediatrician or pediatric neurologist should investigate all cases of

Moderate to severe developmental delays

Progressive disability

Neuromuscular deterioration

Suspected seizure disorders

Diagnosis of cause

History (including perinatal, developmental, neurologic, and familial) may identify causes ( 1 ).

Cranial imaging (eg, MRI) can show central nervous system malformations (as seen in neurodermatoses such as neurofibromatosis or tuberous sclerosis), treatable hydrocephalus, or more severe brain malformations such as schizencephaly.

Genetic tests may help identify disorders:

Standard karyotyping shows Down syndrome (trisomy 21) and other disorders of chromosome number.

Chromosomal microarray analysis identifies copy number variants such as might be found in 5p- syndrome (5p minus syndrome or cri du chat syndrome) or DiGeorge syndrome (chromosome 22q deletion).

Direct DNA studies identify Fragile X syndrome.

Chromosomal microarray analysis is the preferred investigative tool; it can be used to identify specifically suspected syndromes and also when no specific syndrome is suspected. It affords opportunities for identifying otherwise unrecognized chromosome disruptions but requires parental testing to interpret positive findings. Whole genome sequencing of the coding regions (whole exome sequencing) is a more detailed method that may uncover additional causes of intellectual disability.

Clinical manifestations (eg, failure to thrive, lethargy, vomiting, seizures, hypotonia, hepatosplenomegaly, coarse facial features, abnormal urinary odor, macroglossia) may suggest a genetic metabolic disorder . Isolated delays in sitting or walking (gross motor skills) and in pincer grasp, drawing, or writing (fine motor skills) may indicate a neuromuscular disorder .

Specific laboratory tests are done depending on the suspected cause (see table Tests for Some Causes of Intellectual Disability ). Visual and auditory assessments should be done at an early age, and screening for lead exposure is often appropriate.

Diagnosis reference

1. Moeschler JB, Shevell M; Committee on Genetics : Comprehensive evaluation of the child with intellectual disability or global developmental delays.  Pediatrics 134(3):e903–e918, 2014. doi:10.1542/peds.2014-1839

Treatment of Intellectual Disability

Early intervention program

Multidisciplinary team support

Treatment and support needs depend on social competence and cognitive function. Referral to an early intervention program during infancy may prevent or decrease the severity of disability resulting from a perinatal insult. Realistic methods of caring for affected children must be established.

Family support and counseling are crucial. As soon as intellectual disability is confirmed or strongly suspected, the parents should be informed and given ample time to discuss causes, effects, prognosis, education and training of the child, and the importance of balancing known prognostic risks against negative self-fulfilling prophecies in which diminished expectations result in poor functional outcomes later in life. Sensitive ongoing counseling is essential for family adaptation. If the family’s physician cannot provide coordination and counseling, the child and family should be referred to a center with a multidisciplinary team that evaluates and serves children with intellectual disability; however, the family’s physician should provide continuing medical care and advice.

A comprehensive, individualized program is developed with the help of appropriate specialists, including educators.

A multidisciplinary team includes

Neurologists or developmental-behavioral pediatricians


Physical therapists and occupational therapists (who assist in managing comorbidities in children with motor deficits)

Speech pathologists and audiologists (who help with language delays or with suspected hearing loss)

Nutritionists (who help with treatment of undernutrition)

Ophthalmologists or optometrists (who help ensure optimal vision)

Social workers (who help reduce environmental deprivation and identify key resources)

Psychologists (who oversee planning of behavioral interventions)

Affected children with concomitant mental health disorders such as depression may be given appropriate psychoactive medications in dosages similar to those used in children without intellectual disability. Use of psychoactive medications without behavioral therapy and environmental changes is rarely helpful.

Every effort should be made to have children live at home or in a community-based residence. Living at home with the family is usually better for the child than alternative placements unless marked behavior difficulties require a higher level of supervision than the family can provide. The family may benefit from psychological support and help with daily care provided by day care centers and respite services. The living environment must encourage independence and reinforce learning of skills needed to accomplish this goal.

Whenever possible, children with intellectual disability should attend an appropriately adapted day care center or school with peers without cognitive disability. The Individuals with Disabilities Education Act (IDEA) , the primary law regarding special education in the United States, stipulates that all children with disabilities should receive appropriate educational opportunities and programs in the least restrictive and most inclusive environments. The Americans with Disability Act and Section 504 of the Rehabilitation Act also provide for accommodations in schools and other public settings.

As people with intellectual disability reach adulthood, an array of supportive living and work settings is available. Large residential institutions are being replaced by small group or supported individual residences matched to the individual's functional abilities and needs.

Prognosis for Intellectual Disability

Many people with mild to moderate intellectual disability can support themselves, live independently, and be successful at jobs that require basic intellectual skills.

Life expectancy may be shortened, depending on the etiology of the disability, but health care is improving long-term health outcomes for people with all types of developmental disabilities. People with severe intellectual disability are more likely to require life-long support. The more severe the cognitive disability and the greater the immobility, the higher the mortality risk.

Prevention of Intellectual Disability

Vaccines have all but eliminated congenital rubella and pneumococcal and H. influenzae meningitis as causes of intellectual disability.

Fetal alcohol syndrome is a highly common and preventable cause of intellectual disability. Because it is unknown when during pregnancy alcohol is most likely to harm the fetus and whether there is a lower limit of alcohol use that is completely safe, pregnant patients should be advised to avoid all alcohol intake.

prevention of congenital neurologic anomalies ).

Continuing improvements in, and increased availability of, obstetric and neonatal care and the use of exchange transfusion and Rho(D) immune globulin to prevent hemolytic disease of the newborn have reduced the incidence of intellectual disability; the increase in survival of very low-birth-weight infants has kept the prevalence constant.

Intellectual disability involves slow intellectual development with subaverage intellectual functioning, immature behavior, and limited self-care skills that in combination are severe enough to require some level of support.

A number of prenatal, perinatal, and postnatal factors can cause intellectual disability, but a specific cause often cannot be identified.

Deficits in language and personal–social skills may be due to emotional problems, environmental deprivation, learning disorders, or deafness rather than intellectual disability.

Screen using tests such as the Ages and Stages Questionnaire (ASQ) or the Parents’ Evaluation of Developmental Status (PEDS) and refer suspected cases for standardized intelligence testing and neurodevelopmental assessment.

Search for specific causes with cranial imaging, genetic tests (eg, chromosomal microarray analysis, exome sequencing), and other tests as clinically indicated.

Provide a comprehensive, individualized program (including family support and counseling) using a multidisciplinary team.

More Information

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

American Academy of Pediatrics: Comprehensive evaluation of the child with intellectual disability or global developmental delays (2014)

Individuals with Disabilities Education Act (IDEA) : A United States law that makes available free appropriate public education to eligible children with disabilities and ensures special education and related services to those children

Americans with Disability Act : A United States law that prohibits discrimination based on disability

Section 504 of the Rehabilitation Act : A United States law that guarantees certain rights to people who have disabilities

American Association on Intellectual and Developmental Disabilities (AAIDD): An organization providing research, support, and advocacy resources for people with intellectual and developmental disabilities

March of Dimes : An organization aiming to improve the health of mothers and babies through research, advocacy, and education


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  • What is Intellectual Disability?

Intellectual disability 1  refers to neurodevelopmental conditions that affect functioning in two areas:

  • Cognitive functioning, such as learning, problem solving and judgement.
  • Adaptive functioning, activities of daily life such as communication skills and social participation.

Additionally, the intellectual and adaptive deficit begin early in the developmental period, typically before age 18 years for diagnosis.

Intellectual disability affects about 1% of the population, and of those about 85% have mild intellectual disability. In high-income countries, 2–3% of children have an intellectual disability.

Diagnosing Intellectual Disability

Intellectual disability is identified by significant limitations in both intellectual functioning and adaptive behavior.

Intellectual functioning is measured with individually administered and psychometrically valid, comprehensive, culturally appropriate, psychometrically sound tests of intelligence. While a specific full-scale IQ test score is no longer required for diagnosis, standardized testing is used as part of diagnosing the condition. A full-scale IQ score of around 70 to 75 indicates a significant limitation in intellectual functioning. 2 However, the IQ score must be interpreted in the context of the person’s difficulties in general mental abilities. Moreover, scores on subtests can vary considerably so that the full-scale IQ score may not accurately reflect overall intellectual functioning. Therefore, clinical judgment is needed in interpreting the results of IQ tests.

What is intellectual functioning? Intellectual functioning incorporates the characteristics of intelligence, the abilities assessed by standardized intelligence tests, and the consensus view that intellectual functioning is influenced by other human functioning dimensions and by systems of supports.

Traditionally, cognitive or intellectual functioning has been measured through the intelligence quotient (IQ) tests, with an IQ of less than 70 recommended for a clinical diagnosis of Intellectual Disability. Currently, clinical diagnosis also requires a score of two or more standard deviations below the population norm (approximately less than the 2nd/3rd percentile) on a standardized measure of adaptive skills such as the vineland adaptive behavior scales.

What is adaptive behavior? Adaptive behavior is the collection of conceptual, social, and practical skills that have been learned and are performed by people in their everyday lives, which include the following:

Three areas of adaptive functioning are considered: 3

  • Conceptual – language, reading, writing, math, reasoning, knowledge, memory.
  • Social – empathy, social judgment, communication skills, the ability to follow rules and the ability to make and keep friendships.
  • Practical – independence in areas such as personal care, job responsibilities, managing money, recreation, and organizing school and work tasks.

Adaptive functioning is assessed through standardized measures with the individual and interviews with others, such as family members, teachers and caregivers.

Age of onset is the third element for a diagnosis of ID. This third criterion is essential because it establishes the age-related parameters for determining when ID originates or is first manifested. The age of onset criterion “before the individual attains age 22” found in the 12th edition of the AAIDD Manual is based on recent research showing that important brain development continues into our 20s.

The clinical symptoms and signs of intellectual disability are first recognized during infancy and childhood. Intellectual disability is identified as mild (most people with intellectual disability are in this category), moderate, or severe or profound.

There are many different causes of intellectual disability. It can be associated with a genetic syndrome, such as Down syndrome or Fragile X syndrome. It may develop following an illness such as meningitis, whooping cough or measles; may result from head trauma during childhood; or may result from exposure to toxins such as lead or mercury. Other factors that may contribute to intellectual disability include brain malformation, maternal disease and environmental influences (alcohol, drugs or other toxins). A variety of labor- and delivery-related events, infection during pregnancy and problems at birth, such as not getting enough oxygen, can also contribute.

Intellectual disability is a life-long condition. However, early and ongoing intervention may improve functioning and enable the person to thrive throughout their lifetime. Underlying medical or genetic conditions and co-occurring conditions frequently add to the complex lives of people with intellectual disability.

Once a diagnosis of intellectual disability is made, help for individuals with intellectual disability is focused on looking at the individual’s strengths and needs, and the supports he or she needs to function at home, in school/work and in the community.

Services for people with intellectual disabilities and their families can provide support to allow full inclusion in the community. Many different types of treatments and services can help, such as:

  • Treatment of medical complications.
  • General preventive medical care.
  • Treatment of co-morbid medical and mental health conditions.
  • Treatment of challenging behaviors.
  • Rehabilitation services.
  • Early intervention (infants and toddlers).
  • Special education.
  • Family support (for example, respite care support groups for families).
  • Transition services from childhood to adulthood.
  • Vocational programs.
  • Day programs for adults.
  • Housing and residential options.
  • Case management.

Under federal law (Individuals with Disabilities Education Act, IDEA, 1990), early intervention services work to identify and help infants and toddlers with disabilities. Federal law also requires that special education and related services are available free to every eligible child with a disability, including intellectual disability.

In addition, supports can come from family, friends, co-workers, community members, school, a physician team, or from a service system. Job coaching is one example of a support that can be provided by a service system. With proper support, people with intellectual disabilities are capable of successful, productive roles in society.

A diagnosis often determines eligibility for services and protection of rights, such as special education services and home and community services. The American Association of Intellectual and Developmental Disabilities (AAIDD) stresses that the main reason for evaluating individuals with intellectual disabilities is to be able to identify and put in place the supports and services that will help them thrive in the community throughout their lives.

Tips for Parents

  • Ask for help, learn about your child’s disability.
  • Connect with other parents of children with disabilities.
  • Be patient; learning may come slower for your child.
  • Encourage independence and responsibility.
  • Educate yourself on the educational services your child deserves.
  • Learn the laws that are written to help your child live their best life.
  • Look for opportunities in your community for social, recreational and sports activities (such as Best Buddies or Special Olympics).

Related Conditions

Some mental health, neurodevelopmental, medical and physical conditions frequently co-occur in individuals with intellectual disability, including autism spectrum disorder, cerebral palsy, epilepsy, attention-deficit hyperactivity disorder , impulse control disorder , and depression and anxiety disorders . Identifying and diagnosing co-occurring conditions can be challenging, for example recognizing depression in an individual with limited verbal ability. Family caregivers are very important in identifying subtle changes. An accurate diagnosis and treatment are important for a healthy and fulfilling life for any individual.

  • Autism spectrum disorder
  • Attention-deficit hyperactivity disorder
  • Impulse control disorder
  • Anxiety disorders


  • The term intellectual disability used in DSM-5-TR replaces “mental retardation” used previously.
  • The majority of people, 68%, have IQ scores between 85 and 115.
  • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-Text Revision. Arlington, VA APA Publishing. 2022.
  • Totsika V, Liew A, Absoud M, Adnams C, Emerson E. Mental health problems in children with intellectual disability. Lancet Child Adolesc Health. 2022 Jun;6(6):432-444. doi: 10.1016/S2352-4642(22)00067-0.
  • Schalock, R. L., Luckasson, R., and Tassé, M. J. 2021. Twenty questions and answers regarding the 12th edition of the AAIDD manual: Intellectual disability: definition, diagnosis, classification, and systems of supports. American Association on Intellectual and Developmental Disabilities.
  • Schalock, Robert L., et al. 2021. Intellectual Disability: Definition, Diagnosis, Classification, and Systems of Supports . 12th edition., American Association on Intellectual and Developmental Disabilities (AAIDD). ISBN-13: 978-0-9983983-6
  • Patel DR, Cabral MD, Ho A, Merrick J. A clinical primer on intellectual disability. Transl Pediatr. 2020 Feb;9(Suppl 1):S23-S35. doi: 10.21037/tp.2020.02.02.

Physician Review

Rubí E. Luna, M.D. UCLA Semel Institute for Neuroscience and Human Child and Adolescent Psychiatry Fellow, PGY-5

More on Intellectual Disability

  • The Arc: for People with Intellectual and Developmental Disabilities
  • United Cerebral Palsey - Resource Guide
  • US Department of Education Center for Parent Information and Resources – Intellectual Disability

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Mental Retardation and Intellectual Disability

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research on intellectual disabilities (mental retardation) indicates that

  • David L. Nelson 4  

Cognitive or intellectual disability (ID) in humans is a common trait that has a genetic etiology in as many as one-half of cases. Genetic causes range from single-gene defects to trisomies. The discovery of mutations that lead to ID has led to improved diagnosis and the opportunity for reproductive decisions based on prenatal diagnosis. In addition, understanding the gene defects in ID has elucidated molecules and pathways important for normal cognition, assisting with efforts to understand brain function. This chapter touches on the definition and history of ID, then considers in detail several classifications of gene defects that lead to ID. These include unbalanced gene dosage, with attention to Down syndrome and Prader-Willi and Angelman syndromes, and single gene disorders, particularly X-linked disorders Fragile X and Rett syndromes. Each disorder illustrates important principles in human genetics. Future directions in gene discovery, mutation detection and treatment are discussed.

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research on intellectual disabilities (mental retardation) indicates that

Syndromes of Intellectual Disability

research on intellectual disabilities (mental retardation) indicates that

Genetic Syndromes Associated with Intellectual Disabilities

research on intellectual disabilities (mental retardation) indicates that

What Is New in Genetics and Genomics?

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Nelson, D.L. (2010). Mental Retardation and Intellectual Disability. In: Speicher, M.R., Motulsky, A.G., Antonarakis, S.E. (eds) Vogel and Motulsky's Human Genetics. Springer, Berlin, Heidelberg.

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Intellectual Disability: Definition, Symptoms, Traits, Causes, Treatment

Toketemu has been multimedia storyteller for the last four years. Her expertise focuses primarily on mental wellness and women’s health topics. 

research on intellectual disabilities (mental retardation) indicates that

Shaheen Lakhan, MD, PhD, is an award-winning physician-scientist and clinical development specialist.

research on intellectual disabilities (mental retardation) indicates that

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An intellectual disability is a  neurodevelopmental condition  that develops in childhood. It affects your capacity to learn and retain new information, and it also affects everyday behavior such as social skills and hygiene routines. People with this condition experience significant limitations with intellectual functioning and developing adaptive skills like social and life skills.

An IQ test determines whether a person has an intellectual disability.  IQ scores lower than 70 indicate an intellectual disability. The severity of the condition can range from mild to profound.

  • Mild intellectual disability : A majority of people with intellectual disability experience a mild to moderate form. They can learn practical life skills and function daily with minimal support. However, they might struggle to understand how things work and develop social skills.
  • Severe intellectual disability : With severe intellectual disability, your child might experience significant developmental delays. They need more support than children with mild intellectual disabilities and have limited communication skills.
  • Profound intellectual disability : Children with profound intellectual disability often find it especially difficult to communicate and have difficulty performing physical activities. They are also more likely to develop associated medical conditions. They typically require round-the-clock care and support.

Children with a mild intellectual disability can live a fully functioning life with proper support. However, children with a severe intellectual disability require more extensive and constant support. This condition used to be referred to as mental retardation, which took on a negative connotation in society and was replaced with intellectual disability. This term is less offensive and communicates the severity of the condition.

Intellectual disability is one of the most common developmental disabilities in children. It's estimated that around 6.5 million Americans have an intellectual disability.  

Types of Intellectual Disabilities

There is a range of conditions typically classified as intellectual disability. Some of the most common include:

  • Fragile X syndrome : This is a genetic condition caused by a mutation in the X chromosome. It is the most common type of inherited intellectual disability. Its symptoms include speech problems, sensory issues, and behavioral changes.
  • Down syndrome : Down syndrome is one of the most common forms of intellectual disability. The condition causes a person to develop an extra chromosome which changes how the brain and body develop. People with Down syndrome have distinct physical features that are a marker of the condition. They might have a flattened face and nose, small ears, hands and feet, a short neck, and almond-shaped eyes. They typically have lower than average IQs and experience developmental delays.
  • Prader-Willi syndrome (PWS) : This is a rare genetic condition that affects a child's mental and physical development. A key feature of this disorder is hyperphagia, otherwise known as chronic eating. This causes many children with the condition to develop obesity. Other symptoms include weak muscle tone, behavioral problems, and intellectual delays.
  • Fetal alcohol spectrum disorders (FASDs): Fetal alcohol spectrum disorders refer to a range of conditions caused by alcohol abuse while pregnant. However, consuming even small amounts of alcohol when pregnant could cause the condition . Common symptoms of FASDs include visual or hearing problems, abnormal facial features, lower IQ, and cognitive difficulties.
  • Autism : Autism is a neurodevelopmental condition that causes social, behavioral, and communication challenges. It's unclear what causes the condition to develop, and however, a combination of genetic and environmental factors is suspected. Some common symptoms include being unable to make eye contact, lack of interest in social interactions, non-verbal communication, and sensory sensitivities.

Symptoms of an Intellectual Disability 

Symptoms of intellectual disability will typically start to surface in early childhood. In some cases, these signs might be physical. You might notice your child has an unusually large or small head, abnormalities with their hands or feet, or other physical differences. However, this isn't always the case.

Children who appear physically healthy and normal could also have an intellectual disability. Children who have severe intellectual disability might begin to exhibit symptoms at an earlier age than those with a milder form. If you are worried your child might have an intellectual disability, here are some of the early signs to look out for:  

  • Difficulty speaking 
  • Beginning to move around later than other children 
  • Trouble following simple instruction 
  • Struggling to develop social skills 
  • Delayed motor skills 
  • Seizures 
  • Temper tantrums 
  • Aggressive behavior 
  • Struggling to remember things 
  • Difficulty problem solving 
  • Difficulty developing social skills 
  • Difficulty expressing emotions 
  • Being unable to carry out personal care like getting dressed or taking a bath 

Identifying an Intellectual Disability 

To diagnose an intellectual disability, the following criteria must be met:

  • Limited intellectual functioning : This is typically measured with an IQ test. A test score lower than 70 is usually indicative of limited intellectual functioning. 
  • Limited adaptive skills : Here, a person with an intellectual disability will struggle with social and practical skills needed for daily functioning. These include conceptual skills like reading or writing, social skills like communication or problem solving, and practical skills like eating, walking, or getting dressed. 
  • The onset of symptoms before the age of 18: This condition typically develops in childhood. While it ranges in severity, some early signs delayed motor skills, struggle with problem-solving, difficulty remembering things, and delayed speech. 

Some research shows that about 20-35% of people who have an intellectual disability are also likely to develop other mental health conditions like  anxiety or depression . In determining your child's diagnosis, several tests might be ordered by your healthcare provider and the team of specialists taking care of your child. These tests include: 

  • Neurological tests such as an electroencephalogram (EEG) or magnetic resonance imagining (MRI) to determine if there are any abnormalities in the brain
  • Genetic tests to help identify if there is an  inherited disorder like Fragile X syndrome that could cause intellectual disability
  • General medical tests depending on the symptoms your child is exhibiting
  • Special education tests 
  • Developmental screening tests to determine your child's level of intellectual and social functioning
  • Prenatal screening to determine if there are any developmental challenges while a parent is still pregnant
  • A hearing evaluation in case a hearing problem is responsible for the impaired intellectual functioning and not an intellectual disability. 

Causes of Intellectual Disabilities 

Anything that interferes with the proper growth and development of a child could cause an intellectual disability. It can be challenging to identify the specific cause of your child's intellectual disability in some cases. Several culprits could be responsible for the development of an intellectual disability. Some of the most common include:  

  • Pregnancy complications 
  • Genetics  
  • Childhood illnesses that affect brain development 
  • Environmental factors like pollution
  • Severe emotional or physical abuse 
  • Malnutrition 
  • Being born prematurely 
  • Chromosomal abnormalities like Down syndrome 
  • Head injuries  

Treatment for an Intellectual Disability  

There is no one-fix treatment for intellectual disability. The condition is a lifelong one that will need continuous management. The key to proper treatment is early intervention. Getting an accurate diagnosis and treatment plan once you notice the condition's early symptoms is crucial.

Treatment comes in the form of support and care to improve the daily functioning of a person living with the condition. There is presently no cure for intellectual disability. The main aim of treatment is to improve the daily functioning of a person with this condition. 

Coping With an Intellectual Disability

It's essential to remember that children with intellectual disabilities have the same needs as any other child. Keeping them amongst their peers and exposing them to regular childhood activities is vital for their development. Parents of children with intellectual disabilities often feel the need to keep them secluded to protect them from ridicule or bullying. However, this doesn't help with the development of their social skills.

If you are the parent of a child living with an intellectual disability, here are some things you could do to make sure your child is living a healthy and fully functioning life: 

  • Join a support group : A support group of parents and people living with this condition can provide a wealth of reliable information and emotional support. 
  • Learn more about the condition : It's essential to take time to do your research and learn as much about the condition your child is dealing with as you can. 
  • Don't rush the process : Intellectual disability is a lifelong condition. The process for your child's treatment can take a long while before you see any progress. In severe cases, don't expect your child to make rapid progress. 
  • Stay social : It's vital to maintain your child's social life if they've been diagnosed with the condition. Isolating them can exacerbate their symptoms. 
  • Take part in their treatment : During your child's treatment, they'll work with a host of child care specialists to improve their functioning. It's crucial to be a part of this process. 

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Boat TF, Wu JT, Disorders C to E the SSIDP for C with M, et al. Clinical Characteristics of Intellectual Disabilities. National Academies Press (US); 2015.

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Stefanovic S, DeMarco BA, Underwood A, Williams KR, Bassell GJ, Mihailescu MR. Fragile X mental retardation protein interactions with a G quadruplex structure in the 3'-untranslated region of NR2B mRNA .  Mol Biosyst . 2015;11(12):3222-3230. doi:10.1039/c5mb00423c

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MSD Manual Consumer Version. Intellectual disability - children’s health issues .

By Toketemu Ohwovoriole Toketemu has been multimedia storyteller for the last four years. Her expertise focuses primarily on mental wellness and women’s health topics.

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Physical activity of adults with mental retardation: review and research needs


  • 1 School of Physical Education, Faculty of Education, University of Victoria, PO Box 3015 STN CSC, Victoria, British Columbia V8W 3P1, Canada. [email protected]
  • PMID: 16977907
  • DOI: 10.1177/089011710602100103

Objective: To characterize physical activity levels of adults with mental retardation and identify limitations in published research.

Data sources: Key word searches for "mental retardation," "intellectual disability," "learning disability," or "developmental disability" combined with "physical activity" or "habitual exercise" identified articles from MEDLINE, Academic Search Elite, Psych Articles, Health Source, and SPORT Discus. This produced a total of 801 citations.

Study inclusion and exclusion criteria: Published English-language literature that quantitatively measured physical activity levels of adults with mental retardation was included in this review. Fourteen articles met this criterion.

Data extraction: Characteristics of participants, study design, outcome measures, methods of analyses, and findings in terms of percentages, step counts, and accelerometer output were extracted.

Data synthesis: Data were synthesized to identify the percentage of adults with mental retardation who met published health-related physical activity criteria and compare them with adults without mental retardation and to examine study limitations.

Results: The studies with the greatest rigor indicate that one-third of adults or fewer with mental retardation were sufficiently active to achieve health benefits. However, data are insufficient to determine whether adults with mental retardation are less active than the general community.

Conclusions: Future research would be enhanced by including appropriately powered representative samples, by including comparison groups, by validating physical activity questionnaires, and by determining the accuracy of proxy respondents.

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Exceptional learners.

  • Daniel P. Hallahan , Daniel P. Hallahan University of Florida; University of Virginia
  • Paige C. Pullen , Paige C. Pullen University of Florida
  • James M. Kauffman James M. Kauffman University of Virginia
  •  and  Jeanmarie Badar Jeanmarie Badar Independent Scholar
  • Published online: 28 February 2020

Exceptional learners is the term used in the United States to refer to students with disabilities (as well as those who are gifted and talented). The majority of students with disabilities have cognitive and/or behavioral disabilities, that is, specific learning disability (SLD), intellectual disability (ID), emotional disturbance, (ED), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD). The remaining have primarily sensory and/or physical disabilities (e.g., blindness, deafness, traumatic brain injury, cerebral palsy, muscular dystrophy).

Many of the key research and policy issues pertaining to exceptional learners involve their definitions and identification. For example, prior to SLD being formally recognized by the U.S. Department of Education in the 1970s, its prevalence was estimated at approximately 2% to 3% of the school-age population. However, the prevalence of students identified for special education as SLD grew rapidly until by 1999 it reached 5.68% for ages 6 to 17 years. Since then, the numbers identified as SLD has declined slowly but steadily. One probable explanation for the decrease is that response to intervention has largely replaced IQ-achievement as the method of choice for identifying SLD.

The term intellectual disability has largely replaced the classification of mental retardation . This change originated in the early 2000s because of the unfortunate growing popularity of using retard as a pejorative. Although ID used to be determined by a low IQ-test score, one must also have low adaptive behavior (such as daily living skills) to be diagnosed as ID. That is the likely reason why the prevalence of students with ID at under 1% is well below the estimated prevalence of 2.27% based solely on IQ scores two standard deviations (i.e., 70) below the norm of 100.

There are two behavioral dimensions of ED: externalizing (including conduct disorder) and internalizing (anxiety and withdrawal) behaviors. Research evidence indicates that students with ED are underserved in public schools.

Researchers have now confirmed ADHD as a bona fide neurologically based disability. The American Psychiatric Association recognizes three types of ADHD: (a) ADHD, Predominantly Inattentive Type; (b) ADHD, Predominantly Hyperactive-Impulsive Type; and (c) ADHD, Combined Type.

The American Psychiatric Association recognizes two types of ASD: social communication impairment and repetitive/restricted behaviors. The prevalence of ASD diagnosis has increased dramatically. Researchers point to three probable reasons for this increase: a greater awareness of ASD by the public and professionals; a more liberal set of criteria for diagnosing ASD, especially as it pertains to those who are higher functioning; and “diagnostic substitution”—persons being identified as having ASD who previously would have been diagnosed as mentally retarded or intellectually disabled.

Instruction for exceptional children, referred to as “special education,” differs from what most (typical or average) children require. Research indicates that effective instruction for students with disabilities is individualized, explicit, systematic, and intensive. It differs with respect to size of group taught and amount of corrective feedback and reinforcement used. Also, from the student’s viewpoint, it is more predictable. In addition, each of these elements is on a continuum.

  • exceptional children
  • special education
  • Individuals with Disabilities Education Act
  • learning disabilities
  • intellectual disabilities
  • emotional disturbance
  • attention deficit hyperactivity disorder
  • response to intervention
  • evidence-based instruction

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National Research Council (US) Committee on Disability Determination for Mental Retardation; Reschly DJ, Myers TG, Hartel CR, editors. Mental Retardation: Determining Eligibility for Social Security Benefits. Washington (DC): National Academies Press (US); 2002.

Cover of Mental Retardation

Mental Retardation: Determining Eligibility for Social Security Benefits.

  • Hardcopy Version at National Academies Press

Chapter 1 Introduction

Current estimates suggest that between 1 and 3 percent of people living in the United States will receive a diagnosis of mental retardation. This report assesses the process used by the U.S. Social Security Administration (SSA) to identify individuals with cognitive limitations who experience significant problems in their ability to perform work and may therefore be in need of governmental support. It evaluates the existing disability determination process in the context of current scientific knowledge and clinical practice. Mental retardation, a condition characterized by deficits in intellectual capabilities and adaptive behavior, can be particularly difficult to diagnose in the mild range of the disability.


SSA administers two disability programs that provide income and medical benefits to individuals who are either unable to work or to function as expected given their age because of disability. The Disability Insurance (DI) program, which operates under Title II of the Social Security Act, provides monetary payments to formerly employed individuals who have contributed to the Social Security trust fund through Social Security tax on earnings. Certain classes of dependents of insured individuals are also eligible for DI benefits. The Supplemental Security Income (SSI) program, which operates under Title XVI of the Social Security Act, provides payments to individuals (including children younger than 18 years of age) with a disability who have limited income and other resources. Such a person does not have to have been employed or a contributor to Social Security to be eligible for SSI benefits, although a means test is applied to both income and assets.

Disability is defined similarly for both the DI and SSI programs. For all persons applying under the DI program and for adults applying under the SSI program, disability is defined as “the inability to engage in any substantial gainful activity by reason of any medically determinable physical or mental impairment(s) which can be expected to result in death or which has lasted or can be expected to last for a continuous period of not less than 12 months” (Social Security Administration, 2002, p. 4). Standards are different for children younger than age 18. For this group, disability is defined as having a “medically determinable” physical or mental impairment, or combination of impairments that cause “marked and severe functional limitations.” The impairment must be expected to lead to death or to be present for a continuous 12-month period. A medically determinable impairment is one resulting from anatomical, physiological, or psychological abnormalities that can be established by medical evidence that includes signs, symptoms, and laboratory findings; findings must go beyond the individual's subjective complaints.

Disability Determination Process

The application process for DI and SSI benefits can be a long and complicated one. Individuals (or their parents or guardians) may file for disability benefits by telephone, mail, or by visiting the nearest Social Security Office. The nearest Social Security Office can be identified by calling the toll free number (1-800-772-1213; 1-800-325-0778 for TTY calls). An individual can also call the toll free number and make arrangements to complete an application by telephone. SSA will then set up a time for the local Social Security Office to contact the individual and take the application over the telephone. SSA's website ( ) has helpful information about qualification criteria and procedures for filing disability benefits.

The in-person or telephone interview will be conducted by a claims representative of SSA. The claims representative will determine if the technical aspects of disability eligibility or entitlement are met. If the individual is eligible for benefits under the Title II program, or the Title XVI program, or both programs, the medical and vocational material is then forwarded to the state disability determination services (DDS) in the applicant's state. Medical information can include telephone numbers of doctors, hospitals, clinics, and institutions in which the person received treatment, as well as the dates of treatment; names of all medications currently being prescribed; medical records; and laboratory and test results. Vocational information can include summaries of previous work experiences and locations and a copy of a W-2 form.

Trained disability examiners and medical consultants, who will review all the pertinent information and make the determination of disability, staff the DDS. DDS staff may require additional information in making their determinations—for example, information directly from the applicant's treating clinician. DDS staff may require the applicant to undergo an examination conducted by SSA-hired consultative examiners.

DDS staff make the determination of disability based on the questions presented in Box 1-1 .

Sequential Evaluation Process for Disability Insurance and Social Security Income Benefits. Social Security regulations outline the sequential evaluation process used to evaluate applicants for disability benefits. Program rules further note that when (more...)

The box outlines the five-step process for adults and the three-step process for children used to evaluate applicants for disability benefits. Beyond the stepwise determination process, there are several levels of appeal. There can be a hearing before an administrative law judge at SSA, review by SSA's Appeals Council, and ultimately review by the federal courts. Clearly, both the stepwise determination process and the appeals process involve the use of objective and subjective indicators, as well as many judgments on the part of those making the determinations. Such a process inevitably results in errors, which can be of two types: they can incorrectly exclude someone who is legally entitled to benefits or can incorrectly result in benefits for someone who is not entitled to them. Since both types of errors are costly to the individual and to society, it is important to identify the sources of error and to minimize them. Some are inherent in the criteria for disability determination and the assessment instruments used to determine whether the client meets them.

Criteria for Mental Retardation

SSA disability determination for mental retardation requires that the individual have “significantly sub-average general intellectual functioning with deficits in adaptive functioning initially manifested during the developmental period; i.e., the evidence demonstrates or supports onset of the impairment before age 22” (Social Security Administration, 2002, p. 76). Children must also have significantly subaverage general intellectual functioning with deficits in adaptive behavior. Since they are children and under age 22, such findings will have manifested during the developmental period. The Listing of Im pairments, which specifies medical criteria and associated diagnoses, includes separate criteria for adults and for children and adolescents with mental retardation.

Listing 12.05 of Part A lays out criteria for mental retardation; it is closely paraphrased here. In order to be found eligible for benefits due to mental retardation, adults must be mentally retarded as defined above, and must meet one of four requirements:

  • mental incapacity as evidenced by dependence upon others for personal needs (e.g., toileting, eating, dressing, etc.) and an inability to follow simple directions that is so severe that standardized measures of intellectual functioning cannot be administered;
  • valid verbal IQ (VIQ), performance IQ (PIQ), or full-scale IQ (FSIQ) equal to 59 or less;
  • valid VIQ, PIQ, or FSIQ between 60 and 70, and a separate physical or mental impairment that imposes an additional and significant limitation on work-related functioning; or
  • valid VIQ, PIQ, or FSIQ between 60 and 70, along with at least two of the following: (a) marked restriction of activities of daily living, (b) marked difficulties maintaining social functioning, (c) deficiencies of concentration, persistence or pace that results in problems completing tasks in a timely manner, or (d) repeated episodes of decompensation.

Satisfaction of any one of these four criteria in an individual who has mental retardation meets the step 3 criterion of SSA's determination process; i.e., that the individual has a prima facie case of disability that results in an inability to work.

Separate determination criteria have been developed for children and adolescents, which recognize the different processes and effects that mental disorders have on their functioning. Determination criteria for children are further subdivided by age and associated developmental expectations. Criteria are provided for infants and toddlers (e.g., between ages 1 and 3) and three age groups of children and adolescents (e.g., ages 3 to 6, 6 to 12, and 12 to 18). These age criteria are designed to assess the severity of the disability's impact on the child's or adolescent's functioning, with benefits provided for conditions that cause “marked” restrictions, defined as “more than moderate but less than extreme.” On standardized tests, a score that is “two standard deviations below the mean for the test” is evidence of a marked restriction. A score that is three standard deviations below the mean on a standardized test is evidence of an extreme limitation.

Medical criteria for evaluating children with mental retardation are described in Listing 112.05. Like the definition for adults, mental retardation in children for SSA disability purposes is characterized by significantly subaverage general intellectual functioning, with deficits in adaptive functioning. The Listing, again in paraphrase, includes six criteria for assessing severity of the condition:

  • deficiencies in motor development, cognitive/communicative functioning, or social functioning for infants and toddlers; and for children and adolescents, deficiencies in at least two areas that include cognitive/communicative functioning, social functioning, personal functioning, or deficiencies in concentration, persistence, or pace that result in failure to complete tasks in a timely manner;
  • a dependence on others for personal needs that is grossly in excess of age expectations, and an inability to follow directions that is so severe that standardized tests cannot be administered;
  • valid VIQ, PIQ, or FSIQ of 59 or below;
  • valid VIQ, PIQ, or FSIQ between 60 and 70 and a coexisting physical or other mental disorder that significantly impairs functioning;
  • valid VIQ, PIQ, or FSIQ between 60 and 70 and, for infants and toddlers, the failure to attain development expectations for motor, cognitive/communication, and social functioning that is consistent with other children no more than two-thirds of their chronological age; for older children and adolescents, problems with cognitive/communicative function, social function, personal function, or problems with concentration, persistence, or pace; or
  • failure of older infants and toddlers to attain motor, cognitive/ communicative, and social milestones of children no more than two-thirds of their chronological age and another physical or other mental impairment that significantly impairs functioning; for older children and adolescents, problems with cognitive/communicative, social, or personal function or deficiencies in concentration, persistence, or pace that result in the failure to complete tasks in a timely manner and an additional physical or other mental impairment that significantly impairs functioning.

The definition of mental retardation currently used by SSA differs from that used by other professional and health-related organizations. The concept of mental retardation, particularly a recognition that some portion of the population has cognitive deficits that significantly interfere with functioning, is an old one, although the ways in which this has been defined and measured have changed over time. Scheerenberger (1983) reports descriptions of the condition dating from 1500 B.C. in Egypt, in which disabilities of the mind and body due to brain damage were described.

Early definitions of the condition recognized differences in cognition that were associated with impaired functioning. In 1845, Esquirol (quoted in Scheerenberger, 1983) divided mental retardation into two primary categories based on performance on speech and language tasks. Seguin (1866) identified a severe defect in moral development as the primary characteristic of mental retardation.

According to Sheerenberger (1983), the major concepts common to current definitions of mental retardation were being used in the United States by 1900. These include onset during the developmental period (i.e., before age 22), intellectual deficits, and problems coping with the demands of everyday life. In its 1910 classification scheme, the progenitor of today's American Association on Mental Retardation (AAMR) (previously called the Association of Medical Officers of American Institutions for Idiotic and Feeble-minded Persons and the American Association on Mental Deficiency) issued its first formal definition of mental retardation. AAMR defined persons with mental retardation as being feeble-minded, with development arrested at an early age or as evidenced by an inability to manage the demands of daily life or to keep up with peers (Committee on Classification of Feeble-Minded, 1910). Mental retardation was further divided into three levels of impairment: “idiots” had their development arrested at the level of a 2-year-old; “imbeciles” were at the developmental level of a 2- to 7-year-old; and “morons” were at the development of a 7- to 12-year-old.

Subsequent to the adoption of this definition, the field disagreed over whether mental retardation was a constitutional condition or one based on deficits in social competence (Biasini et al., 1999). Edgar Doll, for instance, proposed that mental retardation was a condition of genetic origin that resulted in social incompetence and arrested development (Doll, 1936a). He believed the condition was incurable. In contrast, Kuhlman (1920) proposed that the condition resulted from a subnormal rate of development, suggesting that it was a result of social functioning deficits rather than genetic conditions. Despite these differences in definition, however, they all focused on the inability to perform common behaviors, delays in social development, and low intelligence (Yepsen, 1941).

The 1959 AAMR definition was the first to integrate formally the measurement of intellectual capabilities and adaptive behavior functioning. This definition defined mental retardation as “subaverage general intellectual functioning which originates in the developmental period and is associated with impairment in adaptive behavior” (Jacobson, 1999). Subaverage intellectual functioning was defined as an IQ of 85 or less, with the developmental period extending only up to age 16. Deficits in adaptive behavior were a required part of the definition of the condition, even though there were no formal measures of the construct. AAMR recommended use of the Vineland Social Maturity Scale (Doll, 1953), with a subjective interpretation to be made by the evaluating clinician. A five-level classification scheme was also included for borderline (IQ 67-85), mild (IQ 50-66), moderate (IQ 33-49), severe (IQ 16-32), and profound (IQ <16) levels of retardation.

AAMR changed its definition in 1973, partly in response to concern about the inappropriate overidentification of minority students as mentally retarded. The new definition eliminated the classification of borderline retardation, and changed the upper criterion of scores on intelligence measures from 85 to 70 or below (Grossman, 1973). The result was a significant reduction in the numbers of children eligible for special school services and governmental supports. Levels of retardation were also redefined slightly.

AAMR's definition was revised again in 1977. This change suggested that IQs in the range of 70 to 75 might also be indicative of mental retardation if there were also significant deficits in adaptive behavior (Grossman, 1977). This change took into consideration the standard error of measurement on most tests of intelligence. In its most recent definition, adopted in 1992, AAMR has done away with the levels of retardation (American Association on Mental Retardation, 1992). The organization has also provided a list of 10 adaptive skill areas, with deficits in at least 2 of them required for a diagnosis of mental retardation. This current definition is discussed in more detail below.

The American Psychiatric Association, in its Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), melded the 1977 and 1992 AAMR definitions, retaining the severity levels from 1972 and adopting a list of adaptive behavior areas similar to those chosen by AAMR in 1992. The DSM-IV also kept the upper limit of intelligence at equal to or less than 70.

It is important to note that the differences between the SSA definition of mental retardation and those of the major professional and health-related organizations derive from the purpose for which it is used. The SSA definition is used not for diagnostic purposes, but rather for purposes of program eligibility. The SSA definition fulfills its purpose of identifying individuals with cognitive limitations who experience significant problems in their ability to perform work and may therefore be in need of governmental support.


In the General Population

There are widely disparate prevalence estimates of mental retardation in the U.S. population. Different studies report different rates depending on the definitions used, methods of diagnosis, and the particular population studied. For instance, the DSM-IV estimates the prevalence of mental retardation at 1 percent, although the basis for this number is not provided (American Psychiatric Association, 1994). This estimate is similar to that provided by other researchers (Hodapp & Dykens, 1996). Baroff (1991), using empirical sampling, estimates that 0.9 percent of the U.S. population can be presumed to have mental retardation. In a review of epidemiological studies, McClaren and Bryson (1987) report the prevalence of mental retardation at 1.25 percent, based on total population screening. Among school-age children, the U.S. Department of Education (1994) reports that prevalence estimates provided by different states in determining eligibility for special educational services ranged from 0.3 to 2.5 percent. In contrast, the U.S. surgeon general has estimated that some 7.5 million persons living in the United States have a diagnosis of mental retardation, representing almost 3 percent of the population.

The Centers for Disease Control and Prevention is conducting a longitudinal study called the Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP), which monitors the prevalence of developmental disabilities, including mental retardation, among children 3 to 10 years of age in the metropolitan Atlanta region (Boyle et al., 1996). The study used the definition of mental retardation listed in the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9) (World Health Organization, 1988), which includes severity ratings for mild, moderate, severe, and profound levels of retardation. Findings from the MADDSP indicate an overall prevalence of 8.7 per 1,000 children 3 to 10 years of age in Atlanta. Approximately two-thirds of all cases of retardation were of mild severity. Prevalence of mental retardation varied by age, ranging from 5.2/1,000 for children 3 to 4 years of age to 12.3/1,000 for children 9 to 10 years of age. Increases in prevalence were more likely to occur for children in the mild and moderate ranges of retardation, rather than in the severe and profound ranges.

These rates for children are similar to those reported in analyses of the National Health Interview Survey. Again, using the ICD-9 definition of mental retardation, Halfon and Newacheck (1999) reported unadjusted prevalence rates for mental retardation at 10.5/1,000 for children younger than 18. Analyses further indicated that the prevalence of mental retardation increased with age, ranging from 2.0/1,000 cases for children younger than 6, to 14.7/1,000 cases for children ages 6 to 12, and 15.7/1,000 cases for youth ages 12 to 17. The prevalence of mental retardation was also higher for males (13.0/1,000) than females (7.9/1,000).

Among different racial/ethnic groups, the prevalence of mental retardation was higher among black youth (16.2/1,000) than white (9.8/1,000), Hispanic (9.0/1,000) and other (6.4/1,000) youth. Prevalence rates are higher in some racial/ethnic groups partly because the responses to the National Health Interview Survey are provided by parents, who may have cultural reasons for concealing their child's cognitive disability. The correlation of low socioeconomic status and mental retardation is very high (see Chapter 2 ), and poverty rates are very high among black and Hispanic youth.

These prevalence estimates are vastly different, ranging from a low of 1 percent to a high of almost 3 percent. It is likely that the actual number of individuals with mental retardation ranges between 1 and 3 percent. This suggests that between 2.8 million and 7.5 million individuals could be diagnosed as having mental retardation.

In the Social Security System

Individuals with a diagnosis of mental retardation constitute a significant number of all recipients of SSA disability benefits. Data from SSA's Annual Statistical Supplement (2001a) indicate that as of December 2000, 567,151 persons with a diagnosis of mental retardation were receiving DI benefits, including 257,601 workers, 299,925 children age 18 or older, and 9,625 widows or widowers. Individuals classified as mentally retarded represented 10 percent of all workers with disabilities.

The SSI program has similarly high numbers of recipients with mental retardation. Among children receiving SSI benefits in December 2000, individuals with a mental retardation diagnosis constituted the largest diagnostic group at 32.8 percent (261,200 individuals). Consistent with other epidemiological data, the number of boys (162,230) outnumbered the number of girls (98,880) among children classified as having mental retardation (Social Security Administration, 2001b).

Data from December 2000 also highlight high numbers of adult recipients with mental retardation among SSI beneficiaries (Social Security Administration, 2001a). Among adult SSI recipients, individuals with mental retardation constituted 25.7 percent of all beneficiaries, representing the second largest diagnostic group of recipients (“all other mental disorders” was the largest at 34.4 percent). Males (52.5 percent) outnumbered females (47.5 percent) among SSI recipients with mental retardation.


The current study was designed to assess SSA's disability determination process for mental retardation. The committee was asked to examine new scientific opportunities and associated practice techniques to improve the current determination process. In addition, the committee has been asked to suggest new procedures to respond to these developments. Finally, this study will identify promising research opportunities that might help to clarify unaddressed or incompletely answered questions. SSA is most concerned about accurately diagnosing mental retardation among individuals in the mild range of retardation.

This report draws on recent research advances in the areas of cognition and learning, new information about the neural processes that occur during thinking and learning, and new knowledge about development of learned competencies, such as social skills and practical skills for everyday living. Furthermore, research from decision sciences has been examined to inform SSA's policy making. This study was prompted by a number of issues, including:

  • the adequacy of SSA's definition of mental retardation,
  • questions about intellectual assessment,
  • issues raised by the assessment of adaptive behavior,
  • thinking about how to combine data from intellectual and adaptive behavior assessments, particularly in the mild range of mental retardation, to accurately diagnose the condition, and
  • issues related to distinguishing mental retardation from other diagnoses, particularly for children and adolescents.

Public Policy Implications

The diagnosis of mental retardation, as well as the receipt of benefits, has associated public policy implications. These policy issues relate to the context in which the program operates, as well as the impact of benefit receipt. Recipients get money to help with income maintenance, but they also get health care coverage through Medicaid. This health care coverage allows individuals with chronic medical conditions to receive needed treatment. In response to a number of issues, SSA changed the nature of its definitions of mental retardation and consequently the number of individuals receiving benefits. Any review of current practice has to consider that additional changes, while well meaning, may have negative effects on beneficiaries and the disability program itself. The committee has included an analysis of these issues in its assessment of the current determination system.

Adequacy of the SSA Definition

SSA's definition of mental retardation rests on subaverage intellectual functioning, either alone or in combination with other disabilities or functional impairments. The impairment must be present before the age of 22, although the diagnosis may be made at any time. This definition of mental retardation differs from that of several other organizations, including the American Psychiatric Association in its DSM-IV, the American Association of Mental Retardation, the World Health Organization in its International Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), and Division 33 (Mental Retardation and Developmental Disabilities) of the American Psychological Association.

DSM-IV defines mental retardation as significantly subaverage intellectual functioning (i.e., IQ no higher than approximately two standard deviations below the mean), which is accompanied by significant limitations in adaptive functioning in at least two of the following areas: communication, functional academic skills, health, home living, leisure, safety, self-care, self-direction, social/interpersonal skills, use of community resources, and work. Onset of these conditions must occur before age 18. The condition is further divided into four levels of retardation based on IQ, which include mild mental retardation (IQ between 50-55 and 70), moderate mental retardation (IQ between 35-40 and 50-55), severe mental retardation (IQ between 20-25 and 35-40), and profound mental retardation (IQ below 20 or 25) (American Psychiatric Association, 1994).

For AAMR, mental retardation is defined by substantial limitations in present functioning. It is defined as subaverage intellectual functioning that exists concurrently with deficits in two or more of the following adaptive skill areas: communication, self-care, home living, social skills, community use, self-direction, health and safety, functional academics, leisure, and work. The condition has to be manifested before age 18. AAMR further classifies mental retardation based on the nature and level of support needed by the individual, which can be intermittent, limited, extensive, or pervasive (American Association on Mental Retardation, 1992). These levels of support are not necessarily commensurate with the levels of retardation specified in the DSM-IV.

The World Health Organization (WHO), in its ICD-10, defines mental retardation as a “condition of arrested or incomplete development of the mind, which is especially characterized by impairment of skills manifested during the developmental period, which contribute to the overall level of intelligence, i.e., cognitive, language, motor, and social abilities.” Guidelines suggest that an IQ of less than 70 is indicative of mental retardation. ICD-10 further suggests the use of culturally relevant, standardized measures of social maturity and adaptation for assessing functional abilities. No guidelines are provided, however, on cutoff scores for adaptive behavior deficits. ICD-10 allows for assigning a diagnosis of mental retardation when an individual has both mental retardation and a coexisting mental or physical disorder.

Division 33 of the American Psychological Association has defined mental retardation as “(a) significant limitations in general intellectual functioning; (b) significant limitations in adaptive functioning, which exist concurrently; and (c) onset of intellectual and adaptive limitations before the age of 22 years” (Jacobson & Mulick, 1996). Significant limitations for both intellectual and adaptive functioning are defined as two or more standard deviations below the population mean, using standardized assessment tools.

These definitions differ from those offered by SSA on a number of dimensions. The most significant differences are focused on the age of onset (e.g., 18 versus 22 years of age) and the nature of adaptive functioning deficits and how they are to be measured. WHO and Division 33 advocate the use of a standardized measure of adaptive behavior functioning, while AAMR and the American Psychiatric Association allow for descriptors of functional deficits across different domains. Even with this latter approach, however, the number of areas in which functional limitations must be present also differs. The American Psychiatric Association allows for deficits in at least 2 of their 11 areas, and AAMR specifies deficits in at least 2 of its 10 adaptive skill areas. In contrast, SSA does not specify the number of areas that need to be deficient, relying instead on “marked” restriction of activities of daily living and “marked” difficulties with social functioning. It is worth noting again that SSA uses its definition of mental retardation not for diagnostic purposes, but rather to determine legal eligibility for its benefit programs, in order to ensure that federal resources are used justly and correctly.

Intellectual Functioning and Its Assessment

SSA is similar to the other organizations in the level of intellectual impairment required to be present before a diagnosis of mental retardation can be assigned (i.e., IQ no higher than two standard deviations below the mean). For the other groups, however, that score has to be on the summary score attained on the intellectual functioning measure (e.g., equivalent to Wechsler FSIQ). SSA will also accept part scores from individually administered IQ tests, and specifically mentions Wechsler part scores as examples (e.g., VIQ, PIQ) in its regulations.

While SSA encourages the use of any standardized tests to determine intellectual and adaptive behavior functioning, it does not require these tests. It inadvertently gives preference to the Wechsler tests in its regulations by mentioning that the lowest of the overall summary score (FSIQ) and the two part scores (VIQ and PIQ) may be used in determining intellectual functioning. This not only cements a disparity among measures, without a solid empirical or policy basis, but also begs the question of whether one of these three scores provides the best relevant information. For instance, the FSIQ has higher reliability and validity coefficients than the two part scores. SSA needs to know if current practice and science support a policy of adjudicating on the basis of the lowest of multiple IQs; i.e., FSIQ, VIQ, or PIQ.

SSA further seeks to determine if its cutoff scores of 59 or less and 60 through 70 are also consistent with the current scientific literature on diagnosing mental retardation. The stringent upper limit fails to take into consideration the standard of error of measurement characteristic of all IQ tests. These basic assessment issues are further compounded when tests are administered to a culturally and linguistically diverse population. In some cases, instruments may not be available in a person's native language, or norming procedures may make the instrument inappropriate for use with some culturally and linguistically defined subpopulations.

It is important to know whether the major instruments in the field, such as the Wechsler scales and Stanford-Binet Test of Intelligence, adequately assess intelligence in a given case. If they do not, clinically acceptable and programmatically workable alternative instruments should be explored. This may entail identifying other instruments (including nonverbal intelligence assessment instruments as well as instruments available in languages other than English) that have sufficient reliability and validity to adequately diagnose mental retardation. Of course, any additional instruments identified should have the potential for wide use in clinical practice settings.

A number of research areas have produced reliable findings that are relevant and ready for implementation in practice. Advances in the assessment of developmental functioning have expanded the examination of intelligence from a dependence on verbal and performance intelligence scores to a broader view that incorporates measures of process as well as product. Multiple components that comprise intellectual functioning can now be more easily separated, for example, attentional processes, computational processes, problem-solving skills, and performance processes.

In the area of developmental assessment, standardized preschool measures of competence (Bayley, 1993) are required to assess multiple domains of functioning. These include fine motor, gross motor, cognitive, communication, and social skills. Impairment judgments based only on verbal and performance IQs may not reflect current intelligence testing practices for preschool children. The committee was charged with determining if other instruments better assess young children's intellectual functioning.

Adaptive Behavior Functioning and Its Assessment

For individuals with an intelligence score greater than 59, SSA requires documentation of deficits in adaptive behavior and functioning in order for a classification of mental retardation to be made, as long as no other serious medical condition is present. This may include the results of standardized tests (e.g., Scales of Independent-Behavior-Revised, Vineland Adaptive Behavior Scales) or descriptions from parents, teachers, or treating clinicians. The use of either descriptive evidence or standardized test results seems to reflect variations in practice throughout the field of mental retardation. AAMR and the American Psychiatric Association both allow for behavioral descriptors of adaptive behavior in order to diagnose mental retardation. Division 33 of the American Psychological Association and WHO, however, suggest that results from standardized psychological assessments should be used (Jacobson & Mulick, 1996).

SSA has asked the committee for advice on how best to assess adaptive behavior for eligibility determination and award of benefits. With its current practice, SSA may frequently receive different kinds of information from different sources. The lack of standardization in the assessment of adaptive behavior may lead to a number of difficulties. Currently, claims may be adjudicated on the basis of different kinds of information, and trained lay examiners have the responsibility of combining data from different sources to try and sift out any evidence of deficits in adaptive behavior functioning, working in concert with medical consultants. The result may be inconsistent decision making and a time-consuming determination process.

Other important issues are how well major current measures of communicative, social, personal, motor, and community living skills identify and quantify deficits in adaptive behavior, and how well they meet current standards of reliability and validity. The committee explored alternative approaches that are clinically acceptable and programmatically workable, as well as measures that are currently used but are not satisfactory.

Combining IQ and Adaptive Functioning Data

Describing the nature of behavioral deficits becomes most needed—and most problematic—for individuals whose IQ is close to 70. Currently, SSA combines standardized IQ data with varying kinds of information on adaptive functioning. For adults, disability examiners consider adjustment in occupational and social settings; self-care is also a focus. For children, adjustment, including meeting developmental expectations, is a focus. There are, however, no guidelines about how to consistently combine these two kinds of information.

SSA is interested in the unique contribution each type of measure makes to the analysis of the adjustment of the individual to his or her world. A subset of this issue is the particular contribution of each to the evaluation and diagnosis of mental retardation in borderline situations, i.e., in cases in which the obtained IQ hovers near 70.

Current SSA practices allow a wide role for the qualitative evaluation of performance. Advances in the study of adaptive functioning have provided a more differentiated view of individual social and personal competence. Reviewing current thinking on the multiple dimensions of adaptive functioning could produce new models for such assessment or improve the utility of older assessments by identifying or updating appropriate cutoff scores for disability, or it may point to desirable and justified alterations of functional areas that are the focus of review in the eligibility determination process. The committee has reviewed the practice of allowing qualitative assessments of adaptive functioning, as well as instruments that provide standardized evaluations of adaptive functioning.

Differential Diagnosis

The issue of better differentiating mental retardation from other disorders that may have similar behavioral and cognitive manifestations—called differential diagnosis—is considered last. SSA has had particular difficulty distinguishing mental retardation from other disorders in children and adolescents. The Sullivan v. Zebley decision in 1990, in which the U.S. Supreme Court relaxed the criteria whereby children became eligible for SSI benefits; changes in determination criteria secondary to the Personal Responsibility and Work Opportunity Reconciliation Act of 1996; and the Balanced Budget Act of 1997 have all resulted in criticisms of SSA's attempts to distinguish mental retardation from other cognitive disabilities.

A number of conditions, such as autism, learning disabilities, borderline intellectual functioning, and some organic mental disorders, like traumatic brain injury, are associated with features that overlap with those seen in mental retardation. In addition, some genetic and behavioral disorders share features with mental retardation.

The committee has reviewed these other diagnoses, evaluating the signs and symptoms that are similar to those exhibited by individuals diagnosed with mental retardation, and is providing SSA with suggestions for better distinguishing these cognitive, genetic, and behavioral disorders from mental retardation.

Additional Research Needs

Finally, the process of evaluating scientific evidence generally reviews an area in great detail. The committee summarizes here its finding with respect to additional research that might improve the assessment and diagnosis of mental retardation. It is important to know what research needs to be conducted so that individuals with mental retardation can be better identified and can therefore have access to more appropriate services from education, health, and social service agencies. This question is designed to address the long-term needs of SSA and disability benefit recipients.


The committee and staff cast a wide net in examining the literature on mental retardation and its assessment. This approach was designed to gather information from a wide range of sources and assess the strengths and weaknesses of various pieces of evidence, with a goal of finding convergence of information from descriptive and inferential data and theoretical and conceptual frameworks.

Literature searches were conducted in peer-reviewed journals; technical manuals on intelligence and adaptive behavior measures were reviewed; papers were commissioned from experts on a number of topics central to the committee's work; and feedback was solicited from professional practice, advocacy, and other relevant groups. Members also reviewed technical and policy literature from SSA and other government agencies to get a better sense of the disability programs and benefits provided to individuals with mental retardation. To better understand the practical and policy implications of proposed recommendations on benefit receipt, the committee conducted statistical procedures called Monte Carlo simulations to examine the consequences of altering the criteria for scores on intelligence and adaptive behavior measures. In all of its review work, the committee focused in particular on the area of mild mental retardation, which is most problematic.


This report is focused on specifying criteria for the determination of mental retardation for SSI/DI eligibility purposes. It examines the contextual issues affecting SSA disability benefit programs, with Committee members recognizing that any evaluation of the current determination process for mental retardation is likely to have public policy effects. These effects are discussed in Chapter 2 . SSA's charge to the committee posed several questions. The first, do current IQ tests adequately reflect widely accepted concepts of intelligence, is discussed in Chapter 3 . The second asks how adaptive functioning is best defined and assessed; the committee's detailed response is in Chapter 4 . SSA also asked about the relationship between measures of intelligence and adaptive behavior, which is covered in Chapter 5 . Chapter 6 , on differential diagnosis, explains how the conditions that share signs and symptoms with mental retardation are best distinguished from it. Suggestions for additional research that might shed light on any unaddressed or incompletely resolved issues in the field of mental retardation are mentioned throughout the text and are summarized in Chapter 5 .

In focusing on specifying criteria for the determination of mental retardation for SSI/DI eligibility purposes, this report speaks to the intellectual and adaptive behavior criteria that should be used in making these determinations. The committee's findings, conclusions, and recommendations address initial eligibility determinations, that is, individuals who are first applying for disability benefits. For this reason, the committee has reviewed information that applies to all classes of potential beneficiaries, including children and adolescents and adults.

The committee has not explicitly addressed eligibility redetermination, the process of periodically recertifying eligibility for SSA benefits. The time interval for conducting redeterminations varies according to the medical condition. In general, they are scheduled every 7 years for individuals with conditions unlikely to change; every 3 years for conditions amenable to improvement; and as soon as 18 months for conditions likely to improve in the near future. Redeterminations for mental retardation are conducted every 7 years. Committee members view the standards for intellectual functioning and adaptive behavior assessment outlined in this report as applicable to the redetermination process as well.

  • Cite this Page National Research Council (US) Committee on Disability Determination for Mental Retardation; Reschly DJ, Myers TG, Hartel CR, editors. Mental Retardation: Determining Eligibility for Social Security Benefits. Washington (DC): National Academies Press (US); 2002. Chapter 1, Introduction.
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  • Published: 02 July 2024

Variants in HCFC1 and MN1 genes causing intellectual disability in two Pakistani families

  • Syeda Iqra Hussain 1 ,
  • Nazif Muhammad 1 ,
  • Shahbaz Ali Shah 1 ,
  • Adil u Rehman 1 ,
  • Sher Alam Khan 1 , 2 ,
  • Shamim Saleha 1 ,
  • Yar Muhammad Khan 3 ,
  • Noor Muhammad 1 ,
  • Saadullah Khan 1 &
  • Naveed Wasif 4 , 5  

BMC Medical Genomics volume  17 , Article number:  176 ( 2024 ) Cite this article

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Intellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual functioning and adaptive behavior. Genetic factors contribute to the development of ID phenotypes, including mutations and structural changes in chromosomes. Pathogenic variants in the HCFC1 gene cause X-linked mental retardation syndrome, also known as Siderius type X-linked mental retardation. The MN1 gene is necessary for palate development, and mutations in this gene result in a genetic condition called CEBALID syndrome.

Exome sequencing was used to identify the disease-causing variants in two affected families, A and B, from various regions of Pakistan. Affected individuals in these two families presented ID, developmental delay, and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing.

In an X-linked family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) was identified, while in family B exome sequencing revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sanger sequencing confirmed the segregation of these variants with ID in each family.


The investigation of two Pakistani families revealed pathogenic genetic variants in the HCFC1 and MN1 genes, which cause ID and expand the mutational spectrum of these genes.

Peer Review reports


Genetic aberrations in the human genome suppress the mental growth, leading to neurodevelopmental anomalies. Intellectual disability (ID) with speech delay and behavioral abnormalities ranges in severity from mild to profound, and can be associated with other conditions like epilepsy, sensory impairment, and autism spectrum disorders [ 1 ]. A definitive diagnosis is made based on a person’s IQ test score, calculated below 70 [ 2 ]. Several genes, including HCFC1 and MN1, have been reported in the literature, causing intellectual disability of various intensities.

The Host Cell Factor C1 ( HCFC1 ) gene (OMIM# 300,019) synthesizes a protein called host cell factor C1 (HCFC1). This particular protein plays a crucial role in many cellular processes, encompassing gene transcription, DNA replication, and chromatin remodeling [ 3 ]. The mutations in the HCFC1 gene have been observed to be correlated with the manifestation of genetic disorders, including an X-linked syndrome, known as methylmalonic aciduria and homocysteinemia, cblX type, characterized by cognitive impairments, delays in developmental milestones, and additional neurological indications like behavioral problems [ 4 , 5 , 6 ].

The meningioma-1 ( MN1 ) gene (OMIM# 618,774) is a transcription activator that controls osteoblast proliferation, motility, differentiation, and function in mammals and is essential for the development of the mammalian palate [ 7 ]. C-terminal truncating variants of the MN1 transcriptional factor have been recently reported to cause a distinct phenotype characterized by craniofacial anomalies and partial rhombencephalon synapsis, a rare brain malformation characterized by midline fusion of the cerebellar hemispheres with partial or complete loss of the cerebellar vermis [ 8 ]. The manifestation of this condition, also known as MN1 C-terminal truncation (MCTT) syndrome or CEBALID (Craniofacial deformities, dysmorphic Ears, Brain Abnormalities, Language delay, and Intellectual Disability), results from the dominantly active truncated protein of MN1 rather than haploinsufficiency [ 9 ]. Intellectual disability, developmental delay, hypotonia (low muscle tone), and psychomotor retardation (delayed or impaired motor skills) are hallmarks of CEBALID syndrome. Cutis laxa, facial dysmorphism, and cerebellar abnormalities may also be associated with this syndrome [ 10 ].

The current study aims to investigate the genotype-phenotype correlation of affected individuals in two Pakistani families exhibiting various ID phenotypes. Exome sequencing revealed disease-causing variants in these families, increasing their mutational spectrum.

Materials and methods

Collection of blood samples.

The institutional ethical review board of Kohat University of Science and Technology, Kohat, Pakistan, approved the study (Ref No./KUST/Ethical committee/2191 dated. 06/10/2021), carefully following the recommendations of the Declaration of Helsinki. Two families (A and B) with ID were enrolled in the current study. Family A, from the Karak region of Khyber Pakhtunkhwa, Pakistan, consisted of three generations and presented an X-linked mode of inheritance. Five individuals, including four unaffected individuals (II-1, II-2, III-1, and III-3) and an affected individual (III-2), participated in this study. Family B, showing the autosomal dominant mode of inheritance, was recruited from Khairpur district of Sindh province. Three members participated in the study, including two unaffected individuals (II-2 and III-1) and one affected (III-2). Adults from both families were interviewed to compile the disease history and construct the pedigrees (Fig.  1 A-B). The blood samples were collected into BD Vacutainer ® (BD, Franklin Lakes, NJ, USA) blood collection tubes and preserved after both families gained informed and written consent. Standard phenol-chloroform extraction methods were used to isolate DNA from the blood samples [ 11 ], and the concentration of the extracted DNA was measured using Qubit Fluorometer (Thermo Fisher Scientific Inc., Waltham, MA, USA) to an accuracy of 40 ng/µl.

figure 1

(a) Pedigree of family A showing X-linked pattern of ID and unaffected and affected individuals of the family (b) Pedigree of family B showing autosomal dominant pattern of ID and the unaffected and affected individuals of the family

Whole exome sequencing

DNA samples (Family A-III-2; Family B-III-2) of two intellectually disabled patients belonging to two ethnically different families were used for whole exome sequencing, which was followed by data filtration to remove variances.

Using the xGen Exome Research Panel v2 (consisting of 5’biotin modified 415,115 oligonucleotide probes that span a 34 Mb target region of 19,433 genes) (Integrated DNA Technologies, Coralville, IA, USA), the exonic regions of all 19,433 human genes were obtained. The probes were normalized before pooling to ensure each probe represented in the panel at the correct concentration. After capturing, all captured regions were sequenced using a NovaSeq 6000 system (Illumina, San Diego, CA, USA). We obtained > 98.9% and > 99.2% of target sequences with ≥ 20× and ≥ 10× coverage, respectively. To convert and demultiplex base call sequence files to FASTQ files, bcl2fastq v2.20.0.422 (as NovaSeq files require bcl2fastq v2.19 or higher) ( ) was utilized. After the sequencing, data was aligned to the GRCh37/hg19 human reference genome, variant calling, and annotation were performed using BWA-mem 0.7.17 (Burrows-Wheeler Aligner) (arXiv:1303.3997 [q-bio.GN]) to create BAM files. To generate VCF files, single nucleotide variants and minor insertions/deletions (indel) variant calling were performed on BAM data using GATK best practices (GATK, version 3.8; ) [ 12 , 13 ]. Utilizing depth-of-coverage (DOC) data, Conifer [ 14 ], and 3bCNV ( ) (Dated:16.06.2021), the copy number variant calling was performed. The AutoMap v1.2, which takes the VCF file (containing genotype and allelic depths for the reference and altered allele) as input, mapped the regions of homozygosity (ROH) from the VCF file [ 15 ]. AutoMap gave a text file (which contains detected ROHs) and a pdf file (which includes a graphical representation of ROHs) as an output. It took about 30 s to compute the exome data.

Variants were chosen based on the phenotype of each patient and the ACMG recommendations using the EVIDENCE tool ( ). This approach involves three essential steps: variant filtration, categorization, and similarity score for the patient’s phenotype. In the first step, the 3 billion genome database ( ) and a genome aggregation database (gnomAD; ) were used for allele frequency estimation (Dated:17.06.2021). Gene variants with over 5% allele frequency were filtered out following ACMG recommendations. The Human Gene Mutation Database (HGMD) ( ) Professional 2022.1, Pakistan Genetic Mutation Database (PGMD) ( ), [ 11 ] the Database of Single Nucleotide Polymorphism (dbSNP) ( ), ClinVar ( ), and VarSome [ 16 ] databases were used (Dated:18.10.2021) to assess the variants. Next, each variant related to the medical condition phenotype was evaluated by applying the ACMG standards [ 17 ]. Lastly, human phenotype ontology (HPO) ( ) provided a computational framework for organizing and displaying phenotypic data for further processing, and the resulting data was retrieved to assess the degree of similarity [ 18 , 19 ] with each of the 7000 rare genetic diseases ( ). As per the ACMG recommendations, there was a range of 0 to 10 in the similarity score between the phenotype of each patient and the disease-related symptoms resulting from priority variations. Medical geneticists and doctors then assess potential changes and associated conditions manually. We employed bidirectional Sanger sequencing to confirm the segregation of disease-causing variants within the families.

Prediction and confirmation of structural analyses

Protein structures were retrieved for protein structural analysis from the Alpha Fold protein structure database, accessible online at [ 20 ]. To validate the 3D-modeled structure of the protein and to verify the phi and psi angles, the Ramachandran plot and the ERRAT ( ) were created using Procheck ( ) [ 21 ].

Protein mutagenesis

Chimera ( ) and Biovia Discovery Studio ( simulation/biovia-discovery-studio/) were utilized to ascertain the 3D-structure of the mutant protein, which is significantly different from the wild-type protein. The mutant structure was derived from the wild-type protein. Biovia Discovery Studio examined the structural variations between wild-type and mutant proteins.

Clinical features of family A

The affected individual (III-2) in family A displayed intellectual impairment symptoms such as hypotonia, lethargy, tremor, and developmental delays. A failure to thrive, a long face with a pointed chin, a high forehead, a flat philtrum groove, spasticity, an irregular stride, huge ears that were conspicuous, and nystagmus were all characteristics of his appearance. He displayed a terrible biting habit. He was unable to recognize different types of currencies and perform mathematical calculations. He also exhibited hostile behavior and did not engage in social engagement. The affected individual was observed to engage in actions such as self-biting and self-beating.

Clinical features of family B

The clinical symptoms of III-2 in family B include a significant delay in the development of the child, difficulty speaking verbally, and unique facial traits. These included dolichocephaly, a flat face, thick eyebrows, widely spaced eyes, low-set ears, and a small nose. He also has anomalous hands and feet, such as malformed fingers or toes, joint deformities, or limb length variances. Deformities made it hard for him to grab, grip, walk, or balance. He also showed hyperphagia, or increased hunger and overeating. The patient has poor muscular tone, reducing strength and coordination. The person (IV-2) has a severe cognitive handicap that makes it difficult to learn, understand, and process information. He also had hyperactivity, impulsivity, and social difficulties. He was not able to walk or move and was not able to take care of himself. He was not able to perform the daily life activities and was handicapped. Key clinical findings in Family A and Family B have been mentioned in supplementary Table 1 .

Molecular findings

Exome sequencing of Family A revealed a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) on the X-chromosome. The segregation analysis of the variant revealed that the male individual (II-1 and III-1) were hemizygous wild-type (c.5705G), female individuals (II-2 and III-3) were heterozygous carriers (c.5705G/A), and the affected male individual (III-2) was hemizygous affected confirming the X-linked inheritance pattern of variant (Fig.  2 a-c). Exome sequencing of Family B revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sequencing analysis confirmed the segregation of this variant in the family, consistent with the autosomal dominant inheritance pattern. Unaffected individuals (II-2, III-1) of the family were homozygous wild-type (c.3680G/G), and the affected individual (III-2) was heterozygous affected (c.3680G/A) for this variant (Fig.  2 d-f).

figure 2

(a) Showing the location of HCFC1 gene (q28) on Chromosome X (b) Typical structure of HCFC1 gene comprising 26 exons and showing the location of the missense variant (c.5705G > A; p.Ser1902Asn) in exon-24 (c) Chromatograms of the Hemizygous unaffected individual (II-1) heterozygous carrier (II-2) and hemizygous affected individual (III-2) of Family A. (d) Showing the location of MN1 gene (q12.1) on Chromosome 22 (e) Typical structure of MN1 gene comprising 2 exons and showing the location of the nonsense variant (c.3680G > A; p.Trp1227Ter) in exon-1 (f) Chromatograms of the homozygous unaffected individual (II-2) and heterozygous affected individual (III-2) of Family B

Structural analysis of HCFC1 and MN1 protein

The wild-type HCFC1 and MN1 protein structures were obtained from the Alpha Fold protein structure database. These structures were assessed using ERRAT and PROCHECK. ERRAT analysis showed a High-quality score of 76.1218 and 95.8621 for HCFC1 and MN1 protein structures, demonstrating structure dependability. PROCHECK also showed that 81.0% of Ramachandran plot residues of MN1 protein were in the favorable region. These data confirm the protein structure’s good quality and conformation.

Mutagenesis of HCFC1 protein and its comparison with wild-type

The mutant HCFC1 protein structure was generated through mutagenesis using the chimera technique. The wild-type HCFC1 protein has a serine at position 1902. Mutagenesis in the wild-type HCFC1 protein was created using the Chimera tool by substituting asparagine in place of serine at position 1902 (Fig.  3 ). The wild-type and mutant HCFC1 protein structures were analyzed using Biovia Discovery Studio. Structures were superimposed and evaluated. The substitution of Ser1902Asn in HCFC1 confirmed abnormalities in the protein structure, affecting their wild-type conformation and function (Fig.  3 ).

figure 3

(a) Structure of wild type HCFC1 protein shown in pink and highlighting Ser1902 in black (b) Structure of mutant HCFC1 protein shown in green and highlighting Asn1902 in red (c) superimposed structure of wild type HCFC1 protein showing pink band and Ser1902 residue in black and mutant HCFC1 protein showing green band and Asn1902 residue in red color

Homology modeling of MN1 and its comparison with wild-type

The nonsense variant homology model was created using the SWISS Model. The wild-type MN1 protein has tryptophan at position 1227. A termination codon at position 1227 replaces the tryptophan amino acid in the mutant MN1 protein, terminating the sequence after the 1226 amino acid. Biovia-Discovery Studio evaluated wild-type and mutant MN1 protein structures. Superimposing and examining the structures showed that Trp1227Ter resulted in protein structural alterations. This premature protein truncation changed the protein’s structure and function (Fig.  4 ).

figure 4

(a) Structure of wild type MN1 protein shown in pink and highlighting Ala1226 in black (b) Structure of mutant MN1 protein shown in green and highlighting Ala1226 in red (c) superimposed structure of wild type MN1 protein showing pink band and mutant MN1 protein showing green band indicating the premature truncation of the protein leading to ID phenotypes

Intellectual disability (ID) affects a significant portion of the population, and the role of a substantial number of genetic factors in influencing normal brain functioning has been studied [ 22 ]. X-linked ID has been extensively studied, but it is not the primary cause of ID. Advances in research and technology have improved our understanding of the underlying causes, but the identification of pathogenic genetic variants is still ongoing [ 23 ]. Over 2,500 genes have been linked to ID, primarily caused by autosomal recessive ID [ 24 ]. Tools like homozygosity mapping and next-generation sequencing have been instrumental in these discoveries [ 25 ].

To date, 16 different mutations in HCFC1 have been associated with various neurological abnormalities, including intellectual impairment, and the protein is involved in cellular growth and metabolism [ 3 ]. Previous studies have established a connection between HCFC1 gene mutations and syndromic (cblX) and non-syndromic forms of intellectual impairment. Syndromic patients typically exhibit severe neurological abnormalities, including persistent epilepsy, facial dysmorphia, and intellectual impairment [ 3 ]. In the current study, we observed intellectual disability phenotypes with tremors and developmental delay. The affected individual presented self-beating and self-biting habits and failed to engage socially. The affected individual presented a long face with a pointed chin, a high forehead, a flat philtrum groove, spasticity, an irregular stride, huge ears and nystagmus phenotypes. Non-syndromic individuals with HCFC1 mutations have also been documented, suggesting a potential role for HCFC1 in brain development. The specific location of the mutation within the HCFC1 protein has been found to influence the severity of symptoms and the presence of an overall syndrome [ 4 ]. Previous studies have revealed a connection between HCFC1 gene mutations and a complex disorder with a broad spectrum of symptoms affecting different organs and tissues [ 26 ].

Cobalamin deficiency, or cblX syndrome, is linked to mutations in the HCFC1 gene’s kelch protein interaction domain. Other mutations in other domains of HCFC1 do not lead to cobalamin deficiency, making these kelch domain mutations rare [ 27 ]. For instance, HCFC1 promoter region mutations cause intellectual impairment but no cobalamin-related symptoms. However, mutations in the Kelch domain are always linked to intellectual impairment syndromes that have cobalamin-related symptoms. The p.Ser225Asn mutation once assumed to be a loss-of-function allele but now shown to modulate MMACHC production, but the effect this mutation on the protein function is still unclear [ 28 ].

Furthermore, the p.Ala477Asn variation in the fibronectin domain has been linked to intellectual impairment and facial dysmorphia, but not cobalamin deficiencies. Intellectual disability is commonly related to mutations in HCFC1 ’s essential region [ 28 , 29 ]. The MMACHC promoter is mildly regulated by the p.Gly876Ser variation. Intellectual disability and aberrant brain development have been linked to additional C-terminal polymorphisms, such as p.Ala1756Val and p.Arg2016Trp, but not other traits [ 29 ]. HCFC1 is a potential candidate gene for common partial epilepsy, demonstrating a unique mechanism of proteolysis dysfunction. Different functional roles are attributed to the various HCF-1 domains, with distinct clinical phenotypes linked to each, suggesting specific sub-molecular effects [ 4 , 30 ]. In a previous study, seven hemizygous HCFC1 variants were identified in 11 cases, a finding that was further validated in a cohort of 13 additional cases with six more hemizygous variants. All patients exhibited partial epilepsies without cobalamin disorders. The study highlighted that variants in the proteolysis domain were linked to mild and partial epilepsy, while those in the kelch domain were associated with cobalamin disorders characterized by severe and potentially fatal epileptic encephalopathy. Variants in the primary and acidic domains, on the other hand, were primarily related to intellectual disability [ 31 ].

Meningioma-1 ( MN1 ) controls the proliferation, motility, differentiation, and function of osteoblasts in mammals as a transcription activator [ 32 ]. The brain deformity known as partial rhombencephalon synapsis is a highly uncommon condition defined by the midline fusion of the cerebellar hemispheres midline fusion and the cerebellar vermis’s loss by either a partial or whole extent. To date, 27 variants in the MN1 gene have been reported to cause CEBALID syndrome [ 33 ]. At this point, there have been at least five patients who are documented to have variable craniofacial abnormalities (most of which involve cleft palate) and intellectual deficits [ 34 , 35 , 36 , 37 ]. These patients had deletions in the 22q12.1-q12.2 region that encompass the MN1 gene. In a study that was conducted just a few years ago, a woman who was diagnosed with developmental delay, cleft palate, and an open anterior fontanelle was investigated. The researcher discovered that the woman had a deletion of 2.28 mega-bases that included the NF2 gene, to a loss of 1.61 mega-bases that included the MN1 gene [ 38 ].

Two families from Pakistan, each with identification documentation, were selected and invited to participate in clinical and genetic investigations in the current study. In the family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) was identified in the HCFC1 gene. This variant followed an X-linked inheritance pattern within the family, as confirmed by Sanger sequencing. The effect of the amino acid substitution on the protein structure was analyzed to gain further insights into the functional impact of the variant, which was achieved by comparing and superimposing the mutant and wild-type protein structures of HCFC1. The analysis revealed that the amino acid substitution resulted in altered interactions and a disrupted protein conformation. This alteration in the protein structure led to disorder within the protein. These findings highlight the potential significance of the identified variant in the HCFC1 gene in the context of X-linked inheritance. The observed changes in protein structure and interactions suggest that this variant may contribute to developing specific phenotypic characteristics or disorders within affected individuals in family A. This hemizygous missense variant (c.5705G > A; p.Ser190Asn) of Family A was located in the fibronectin domain (FN3) of the HCFC1 gene. Previous research has revealed two additional pathogenic variants (p.Ala477Asn & p.Arg2016Trp) located in the same FN3 domain of the HCFC1 gene [ 3 ]. The pathogenic variant p.Ala477Asn was linked to intellectual disability and facial dysmorphia but not cobalamin defects [ 27 ]. On the other hand, the pathogenic variant p.Arg2016Trp was associated with intellectual disability and abnormal brain development without other observed phenotypes [ 3 ].

In Family B, an individual presented with a range of symptoms, including intellectual disability, severe developmental delay, poor language skills, dysmorphic facial features, skeletal deformities, hyperphagia, hyperactivity, and severe aggressive behavior. WES identified a novel heterozygous nonsense variant (c.3680G > A; p.Trp1227Ter) in the MN1 gene after the filtration. This variant followed an autosomal dominant inheritance pattern within the family, meaning that affected individuals carried one copy of the variant (c.3680G/A), while unaffected individuals had two copies of the wild-type variant (c.3680G/G). Further analysis was conducted to understand the functional consequences of the identified variant. Structural analysis revealed significant conformational changes in the protein due to the premature stop codon caused by the variant. Additionally, the variant led to a reduction in the length of the protein. These structural changes and protein truncation are believed to contribute to the observed intellectual disability in the affected individual. The disruption of the MN1 gene’s normal function likely plays a role in the manifestation of the various symptoms, including developmental delay, language difficulties, dysmorphic facial features, skeletal deformities, hyperphagia, hyperactivity, and severe aggressive behavior. This finding underscores the importance of understanding the molecular mechanisms underlying intellectual disability and highlights the role of the MN1 gene in normal cognitive development.

This study investigated the genetics of intellectual disability in two families and identified a novel genetic variant related to ID, expanding the genetic spectrum and variability of intellectual disability and improving our understanding of the condition. The use of next-generation sequencing has been beneficial in identifying genetic variants in families with hereditary disorders.

Data availability

We have submitted the variants data in ClinVar repository ( under the accession numbers SCV004801669 and SCV004708216.

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We are indebted to all research participants for their volunteer contribution to the present genetic study. We are thankful to 3Billion for providing us exome sequencing facility for the current study (

Higher Education Commission (HEC), Pakistan partially supported the current research through Indigenous 5000 Ph.D. Fellowship Project Phase-II, Batch-VI (520(Ph-II)/2BS6-162/HEC/IS/2020).

Open Access funding enabled and organized by Projekt DEAL.

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Department of Biotechnology and Genetic Engineering, Kohat University of Science & Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan

Syeda Iqra Hussain, Nazif Muhammad, Shahbaz Ali Shah, Adil u Rehman, Sher Alam Khan, Shamim Saleha, Noor Muhammad & Saadullah Khan

Department of Computer Science and Bioinformatics, Khushal Khan Khatak University, Karak, Pakistan

Sher Alam Khan

Department of Biotechnology, University of Science and Technology, Bannu, Pakistan

Yar Muhammad Khan

Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany

Naveed Wasif

Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

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(1) Study conception and Planning: N.M., S.K., N.W. (2) Samples and Data collection, analysis and interpretation of data: A.u.R., S.A.S., Y.M.K., S.S. (3) Writing of the first manuscript draft and Figures Preparation: S.I.H, N.M. (4) Effective participation in the research guidance: N.M., N.W., S.K., (5) Critical review of the literature: S.I.H, N.M. (6) Bioinformatics analysis: S.I.H, N.M. (6) Manuscript Critical review and Final approval of the manuscript: N.M., N.W., S.K., S.I.H. All authors have read and finalized the manuscript.

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Correspondence to Saadullah Khan or Naveed Wasif .

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Kohat University of Science and Technology, Pakistan’s institutional ethical review board, approved the study through Ref No./KUST/Ethical committee/2191 dated. 06/10/2021. Informed and signed consent were obtained from the participants and the legal guardians of the patients.

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All the study participants and the legal guardians consented to open-access publication using their clinical data, including the images and the molecular data.

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Hussain, S.I., Muhammad, N., Shah, S.A. et al. Variants in HCFC1 and MN1 genes causing intellectual disability in two Pakistani families. BMC Med Genomics 17 , 176 (2024).

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  • Intellectual disability
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