Version May 2024
INTRODUCTION — Intellectual disability (ID) is a neurodevelopmental disorder with multiple etiologies. It is characterized by deficits in intellectual and adaptive functioning of varying severity, presenting before 18 years of age. ID encompasses a broad spectrum of functioning, disability, and strengths [1]. ID affects approximately 1 percent of the population. It is an important public health issue because of its prevalence and the need for support services. Its management requires early diagnosis and intervention, including access to health care and appropriate supports. Identifying a cause enables condition-specific intervention, surveillance, and appropriate counseling, with anticipation of possible medical or behavioral comorbidities [2].
This topic reviews the epidemiology of ID and the evaluation of affected children for a specific cause. Other aspects of ID are discussed separately:
●(See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis".)
●(See "Intellectual disability (ID) in children: Management, outcomes, and prevention".)
TERMINOLOGY — The following terms are used throughout this topic (see "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis", section on 'Terminology'):
●Intellectual disability – Intellectual disability (ID) is a neurodevelopmental disorder characterized by deficits in intellectual and adaptive skills, affecting at least one of three adaptive domains (conceptual, social, and practical) with varying severity (table 1A-B). The older term "mental retardation" is no longer used in clinical practice. The severity of ID is defined according to the level of adaptive impairment and the level of support needed to address impaired adaptive functioning. Standardized intelligence quotient testing is no longer used to classify ID severity.
●Global developmental delay – Global developmental delay (GDD) is the preferred term to describe intellectual and adaptive impairment in infants and children <5 years old who fail to meet expected developmental milestones in multiple areas of functioning. Not all children with GDD meet criteria for ID as they grow older. The term ID is usually applied to children at approximately 5 years of age, but may be applied to children <5 years old who meet ID criteria.
EPIDEMIOLOGY
Prevalence — The prevalence of ID varies substantially among studies due to differences in study design, diagnostic approach, severity of the condition, and population characteristics, such as age. In the general population, the prevalence of ID (with deficits in both adaptive and intellectual functioning) is approximately 1 percent [3-8]. ID is mild in approximately 85 percent of affected individuals.
The prevalence of global developmental delay (GDD) is estimated to be 1 to 3 percent [9]. GDD does not necessarily predict later ID, although there is a strong correlation.
The prevalence of ID varies with age and gender. It is highest in school-age and male individuals. Approximately 20 to 30 percent more males are diagnosed with ID compared with females [10]; however, the gender difference diminishes with more severe ID. The prevalence of mild ID is more variable across populations than severe ID, varying with environmental factors of maternal education, educational access, or opportunities and access to health care [11,12].
Risk factors — Important risk factors for ID include low level of maternal education, advanced maternal age, and poverty [13-15]. Many other risk factors for ID have been identified and they differ somewhat according to the severity of ID.
In a large birth cohort in Tennessee, low level of maternal education was the strongest predictor of mild ID, and a stronger predictor than maternal age [14]. The risk of ID in children of mothers with ≤12 years of education was seven times greater compared with mothers with some post-secondary education, and three times greater than those with a high school diploma. The risk for mild ID was slightly increased in children born to mothers 15 to 19 years old, while the risk of moderate to severe ID was greatest in those born to mothers 40 to 44 years of age.
In a study of children born in California between 1987 and 1994, the risk of unexplained ID was increased among males, low birth weight infants, multiple births, second or later-born children, older maternal age at delivery, and lower maternal level of education [13].
The risk for ID also appears to be associated with advanced paternal age; one study found that paternal age >40 years is associated with an increased risk for mild to moderate ID [16].
CAUSES — The causes of ID are extensive and include conditions that interfere with brain development and functioning. Among the known causes of ID, the majority are genetic abnormalities [17-19].
Metabolic disorders can cause ID or may be comorbid. ID can present alone or with neurologic abnormalities such as epilepsy or structural brain defects, or with other congenital anomalies.
A minority of cases have environmental causes such as teratogens, toxins, infections, trauma, birth asphyxia, and nutritional deficiencies. The timing, dose, and extent of environmental exposure are important [20]. ID causation may be prenatal, perinatal, or postnatal.
Genetic causes — Genetic conditions are increasingly being diagnosed by technologic advances in genetic testing; a specific genetic cause can be identified in >50 percent of individuals with ID referred for evaluation [17,18,21]. The increasing use of next-generation DNA sequencing techniques (eg, whole exome sequencing [WES]) has uncovered many more genes involved in both syndromic and nonsyndromic forms of ID [22]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)
Chromosomal microarray analysis (CMA) is recommended as first-line test for most patients with ID, unless the patient has features suggesting a specific disorder [11,23]. (See 'Chromosomal microarray analysis' below and 'Testing for specific disorders' below.)
Metabolic disorders are often associated with ID and may be causative in up to 3 percent of patients with unexplained ID [24]. Newborn screening advances have been pivotal in the early diagnosis and treatment of affected children. Increasing identification of treatable inborn errors of metabolism (IEM) has enabled specific intervention, functional improvement, or stabilization. Although children with metabolic disorders may present with ID alone, most have additional features (eg, episodic decompensation, undernutrition, seizures, developmental regression, abnormal findings on neurologic examination, and/or hepatomegaly) [25]. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Newborn screening'.)
A genetic abnormality may present as ID alone (nonsyndromic ID), or as ID associated with a syndrome (syndromic ID) [26]. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis", section on 'Syndromic versus nonsyndromic intellectual disability'.)
Detailed information about many genetic syndromes is available by searching for the disorder in the following open-access databases:
●Online Mendelian Inheritance in Man (OMIM)
Some important genetic causes of ID include the following:
Chromosomal abnormalities — Chromosomal aberrations as a group are the most common known cause of ID [11]. Among the genetic causes, cytogenetic abnormalities visible under a light microscope (ie, detectable by G-banded chromosome analysis) account for approximately 15 percent of cases [27]. Nearly all unbalanced chromosomal rearrangements that are cytogenetically visible can cause ID (with the exception of sex chromosome abnormalities). (See 'Testing for specific disorders' below and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Chromosomal analysis'.)
●Down syndrome – Down syndrome, or trisomy 21, is the single most common known genetic cause of ID [11,28]. (See "Down syndrome: Clinical features and diagnosis".)
●Deletion, microdeletion, and duplication syndromes – Genomic disorders resulting from deletions, microdeletions, or duplications of chromosomal material have been recognized as a frequent cause of ID. Many of these chromosomal abnormalities are below the resolution threshold of G-banded chromosome analysis and therefore CMA or fluorescence in situ hybridization (FISH) are required for detection.
Examples of some more common microdeletion syndromes associated with ID include:
•22q11 deletion syndrome (DiGeorge syndrome, also known as Velocardiofacial syndrome) (see "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis")
•7q11.23 deletion syndrome (Williams syndrome) [29] (see "Microdeletion syndromes (chromosomes 1 to 11)", section on '7q11.23 deletion syndrome (Williams syndrome)')
•17p11.2 deletion syndrome (Smith-Magenis syndrome) [30] (see "Microdeletion syndromes (chromosomes 12 to 22)", section on '17p11.2 deletion syndrome (Smith-Magenis syndrome)')
•15q11-13 maternal and paternal deletion syndromes (Angelman and Prader-Willi syndromes) [31] (see "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)' and "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 paternal deletion syndrome (Prader-Willi syndrome)')
•16p11.2 deletion syndrome (see "Microdeletion syndromes (chromosomes 12 to 22)", section on '16p11.2 deletion syndrome')
•1q21.1 deletion syndrome (see "Microdeletion syndromes (chromosomes 1 to 11)", section on 'Distal 1q21.1 deletion syndrome')
•15q13.3 microdeletion syndrome (see "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q13.3 deletion syndrome')
•17q21 microdeletion syndrome (see "Microdeletion syndromes (chromosomes 12 to 22)", section on '17q21.31 deletion syndrome')
Other microdeletion syndromes are reviewed separately. (See "Microdeletion syndromes (chromosomes 1 to 11)" and "Microdeletion syndromes (chromosomes 12 to 22)".)
Single-gene disorders — Monogenic causes of ID can be classified as having autosomal dominant, autosomal recessive, or X-linked inheritance.
Autosomal dominant inheritance — De novo mutations in dominantly inherited genes are an important cause of severe ID [6,32]. Over 700 genes identified to date are known to cause autosomal dominant ID [33]. Several novel disease genes are identified every year using next generation sequencing (NGS).
In patients with ID in whom standard genetic tests (including CMA) fail to identify a cause, next-generation WES can identify new mutations in 16 to 29 percent of cases [17,32,34,35]. "Trio" exome analysis (ie, evaluation of the affected child and both parents) is particularly helpful in identifying de novo mutations, which are the most common genetic cause of ID in nonconsanguineous populations [36]. Severe ID could be caused by de novo variants in approximately 35 to 45 percent of affected children [17,32]. (See 'Whole exome sequencing' below and "Next-generation DNA sequencing (NGS): Principles and clinical applications".)
Some of the genes that have been identified as associated with ID using these techniques include ARID1B, ANKRD11, KMT2A, STXBP1, PURA, ADNP, SYNGAP1, SCN1A, SCN2A, CDK13, DYRK1A, EP300, TCF4, MED13L, KANSL1, EHMT1, KAT6A, KAT6B, KMT2D, SHANK3, FOXP1, and NSD1 [17,22,34,37,38]. Mutations in these genes often cause other comorbidities such as epilepsy, craniofacial dysmorphism, and/or congenital anomalies.
Autosomal recessive inheritance — Autosomal recessive disorders occur particularly in consanguineous families and include many IEM [11,25,26]. Most children with IEM have other features in addition to ID (eg, episodic decompensation, seizures, developmental regression, failure to thrive, abnormal neurologic exam, and/or hepatomegaly). For children with unexplained ID, the yield of metabolic investigations for IEM ranges from 1 to 3 percent (table 2) [21,24,39]. (See 'Metabolic testing' below and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Developmental delay'.)
Other examples of recessive disorders causing ID include mutations in PRSS12, TANGO2, CRBN, CC2D1A, TUSC3, GRIK2, TRAPPC9, ST3GAL3, MED23, ADAT3, METTL23, SLC6A17, NSUN2, MAN1B1, TECR, TAF2, and FBXO31 [40-42]. These disorders are increasingly identified by homozygous mapping and WES, where available. (See 'Whole exome sequencing' below.)
X-linked disorders — Mutations resulting in X-linked ID have been reported in >100 genes and account for 5 to 10 percent of ID in males [43-45]. X-linked disorders are very heterogeneous and occur in syndromic or nonsyndromic forms.
●Fragile X syndrome – The most common X-linked single gene disorder causing ID is fragile X syndrome, which occurs in approximately 2 to 3 percent of males with ID [28,46]. The prevalence of fragile X syndrome in males with ID is approximately twice that of females (due to variability of expression in females carrying a full mutation as a consequence of variation in X-inactivation). (See 'Testing for fragile X syndrome' below and "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)
●MECP2-related disorders – MECP2-related disorders, including Rett syndrome and MECP2 duplication/triplication, are important causes of X-linked ID:
•Rett syndrome – Rett syndrome is a neurodevelopmental disorder caused by mutations in MECP2 that occurs almost exclusively in females. After a period of initially normal development during the first 6 to 18 months of life, girls experience loss of speech and purposeful hand use, and develop stereotypic hand movements, and gait abnormalities. (See 'Testing for specific disorders' below and "Rett syndrome: Genetics, clinical features, and diagnosis".)
•MECP2 duplication syndrome – MECP2 duplication syndrome (also known as Lubs syndrome), is clinically and genetically distinct from Rett syndrome. It is characterized by duplications (or triplication) of the MECP2 gene and is a cause of severe to profound ID in males [47]. Females with MECP2 duplication are usually asymptomatic, although mild to severe cognitive impairment has been described [48,49]. MECP2 duplications account for approximately 1 percent of unexplained X-linked ID [47]. MECP2 duplication is suspected in males who have neonatal hypotonia progressing to spasticity, failure to thrive, severe language impairment, severe to profound ID, and seizures. CMA is the recommended test to identify MECP2 duplications, as MECP2 sequencing tests do not detect duplications. (See 'Chromosomal microarray analysis' below.)
●DDX3X variants – Pathologic variants in the gene DDX3X are responsible for 1 to 3 percent of ID cases in females; affected male individuals have also been reported [50]. ID severity may be mild to severe. Clinical features vary but can include other neurodevelopmental problems (eg, autism spectrum disorder, attention deficit disorder, behavioral problems), abnormal motor tone (hypotonia or spasticity), seizures, structural brain abnormalities, gastrointestinal problems (eg, feeding difficulties, reflux, constipation), and vision problems (eg, refractive errors, strabismus) [50,51].
●Other X-linked disorders – X-linked creatine transporter deficiency, caused by pathologic variants in the SLC6A8 gene, is characterized by mild to severe ID in males, with speech and motor delay, behavioral abnormalities, and seizures [52]. Elevated ratio of creatine/creatinine in urine with normal plasma levels of creatine and guanidinoacetate are suggestive of the diagnosis, which is confirmed with genetic testing.
Some other genetic causes of ID that are X-linked include variants in the genes ABCD1, ARX, RSK2, DMD, OCRL, ATP7A, L1CAM, MED12, and ATRX [53].
Pelizaeus-Merzbacher disease is a rare X-linked hypomyelinating disorder due to duplication in the PLP1 gene [54,55]. It is characterized by progressive motor and intellectual deterioration in males. The diagnosis is established with brain magnetic resonance imaging and CMA testing.
Mitochondrial disorders — Mitochondrial disorders are a heterogeneous group of diseases that are often associated with ID as well as other neurologic, cardiopulmonary, ophthalmologic, or renal findings. These disorders can be caused by mutations in nuclear genes (autosomal recessive, autosomal dominant, X-linked), or molecular defects in the mitochondrial genome (maternally inherited) [56]. (See "Mitochondrial myopathies: Clinical features and diagnosis".)
Environmental causes — ID resulting from environmental causes may be due to prenatal, perinatal, and/or postnatal exposures [57]:
●Prenatal causes – Important nongenetic prenatal causes of ID include congenital (TORCH [toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus, and herpes]) infections and environmental toxins or teratogens (eg, alcohol, lead, mercury, phenytoin, valproate, radiation exposure). (See "Congenital anomalies: Approach to evaluation" and "Overview of TORCH infections", section on 'Clinical features of TORCH infections' and "Fetal alcohol spectrum disorder: Clinical features and diagnosis".)
●Perinatal causes – Perinatal abnormalities that may lead to ID include preterm birth, hypoxia, infection, trauma, and intracranial hemorrhage. ID occurs in 5 to 36 percent of surviving infants born at ≤25 weeks gestation [58]. (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".)
●Postnatal causes – Postnatal and acquired causes of ID may be easier to identify, as they typically occur in a child who was previously normal. Etiologies include accidental or nonaccidental trauma, central nervous system (CNS) hemorrhage, hypoxia (eg, near-drowning), environmental toxins, psychosocial deprivation, malnutrition, intracranial infection, CNS malignancy, or acquired hypothyroidism. If unrecognized and untreated, congenital hypothyroidism may cause intellectual impairment; where newborn screening is available, early screening and treatment has mostly eliminated ID due to congenital hypothyroidism. (See "Clinical features and detection of congenital hypothyroidism".)
Some children with ID may have an etiology that is multifactorial. In these cases, multiple conditions or exposures may act simultaneously or at different times. The relative extent or contribution of multiple conditions or toxins upon outcomes is not known, although insults at younger developmental ages have greater impact.
APPROACH TO DIAGNOSTIC TESTING — Selection and sequence of diagnostic testing to identify a cause in children with ID is guided by a detailed history (including family history), thorough physical examination (including neurologic examination and evaluation for dysmorphic features), and the availability of the specific tests [3,9,23]. A collaborative approach that includes parent participation in the child's evaluation is important. Tests may vary across clinical settings and among nations, especially where screening programs differ [59]. Factors such as the cost-benefit, cost-effectiveness, and the evidence base for specific, sequential, or stepwise testing in evaluation may be considered.
The following sections review the approach to diagnostic testing in children with ID. The approach may differ in children with ID that is associated with autism, cerebral palsy, epilepsy, or sensory disorders (blindness, deafness). These conditions are discussed in separate topic reviews. (See "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis" and "Cerebral palsy: Evaluation and diagnosis" and "Seizures and epilepsy in children: Classification, etiology, and clinical features" and "Hearing loss in children: Etiology".)
Goals of the evaluation — The evaluation is aimed at identifying a particular cause so as to provide more information to the family about the associated prognosis, comorbidities, anticipation of future needs, and whether any specific treatment is available. With the exception of treatable metabolic disorders, most causes of ID do not have specific treatments to rectify the cause. Genetic causes may have implications for future pregnancies, and there may also be reproductive implications for the extended family, which should be addressed with genetic counseling. Even if a specific diagnosis cannot be found, excluding certain disorders may be helpful for the parents and other family members.
Testing for specific disorders — Children with dysmorphic features or other characteristics that suggest a particular syndrome or disorder should undergo specific testing to confirm or rule out that disorder (algorithm 1 and table 3).
Some examples of suspected disorders that are associated with characteristic findings for which specific tests are recommended as the initial step are discussed here. Additional examples are provided in the table (table 3).
●Down syndrome or other common aneuploidy – For children with clinical features suggesting Down syndrome or other common aneuploidy (trisomy 18 or a sex chromosome aneuploidy such as Klinefelter [47,XXY]), we suggest a G-banded karyotype analysis. (See 'Karyotype analysis' below and "Down syndrome: Clinical features and diagnosis" and "Congenital cytogenetic abnormalities" and "Sex chromosome abnormalities".)
●Fragile X syndrome – Fragile X syndrome (full FMR1 mutation) should be suspected in males with moderate to severe ID, macrocephaly, large ears, enlarged testes after puberty, perseverative speech, and gaze aversion. Males with unexplained ID and a family history of ID should also be evaluated for the syndrome. Females with characteristic clinical features or a family history of ID also should be tested for fragile X syndrome because females with full FMR1 mutation present with ID in approximately half of the cases. (See 'Testing for fragile X syndrome' below and "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)
●Rett syndrome – Rett syndrome should be suspected in girls with unexplained moderate to severe ID who had normal development during the first six months of life and then experienced a period of regression or developmental stagnation usually beginning in the second year of life, especially if there are stereotypic hand movements. (See "Rett syndrome: Genetics, clinical features, and diagnosis".)
●Inborn errors of metabolism – ID is a clinical feature of some inborn errors of metabolism (IEM). Most affected children have other manifestations of metabolic disease, such as episodic decompensation, seizures, developmental regression, failure to thrive, abnormal neurologic exam, and/or hepatomegaly. Screening programs in the United States identify many newborns with IEM. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Newborn screening'.)
The results of newborn screening for metabolic disorders should be reviewed as part of the initial evaluation in all children with ID. Additional testing should be performed if these results are not available, or in children with a positive family history of metabolic disorders, parental consanguinity, episodic decompensation, or developmental regression. The presence of these features increases the likelihood of identification of a disorder compared with nonselective screening [60]. (See 'Metabolic testing' below.)
The approach to evaluating children with suspected metabolic disorders is reviewed separately. (See "Inborn errors of metabolism: Identifying the specific disorder".)
●Hypothyroidism – Thyroid testing should be performed in infants and children with clinical features suggestive of hypothyroidism (eg, decelerating growth velocity/short stature, cold intolerance, feeding problems, puffy facies, macroglossia, large fontanels, hypotonia, dry skin, and prolonged jaundice). (See "Clinical features and detection of congenital hypothyroidism", section on 'Clinical manifestations'.)
In addition, thyroid testing is recommended routinely for infants and children presenting with ID in countries without newborn screening programs for congenital hypothyroidism. In these areas, unrecognized congenital hypothyroidism is a more common cause of ID. Most affected patients have additional systemic signs of hypothyroidism.
In countries where newborn screening for hypothyroidism is routinely performed, congenital hypothyroidism is an uncommon cause of ID.
●Muscular dystrophy – For boys with unexplained global developmental delay (GDD) or ID with proximal muscle weakness, we suggest measurement of serum creatine kinase to screen for Duchenne muscular dystrophy. If the creatine kinase is elevated, specific genetic testing is then performed. Boys with Duchenne muscular dystrophy may present with unexplained GDD/ID; screening is appropriate for boys with clinical features that suggest this diagnosis [61,62]. Early identification of this disorder enables early intervention and family counseling. Becker muscular dystrophy also may be associated with ID, but the muscular dysfunction tends to be milder. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)
Unexplained ID — If no specific disorder is clinically suspected or if initial testing for specific disorders is nondiagnostic, then genetic testing for idiopathic or unexplained ID is recommended, starting with a chromosomal microarray analysis (CMA) (algorithm 1) [2,3,9,23].
Rationale for genetic testing — Genetic tests are recommended for unexplained ID because they can provide diagnostic and prognostic information and allow for informative genetic counseling. In addition, genetic testing may identify conditions that require further medical evaluation or management.
A genetic disorder is suggested when unexplained ID occurs in combination with one or more of the following features:
●Family history of consanguinity
●Family history of ID
●Maternal history of multiple miscarriages or family history of infant deaths
●Congenital/visceral anomalies (eg, hearing loss, visual problems, congenital heart defects, vascular abnormalities, skeletal abnormalities, endocrine problems, central nervous system [CNS] malformations, seizures, microcephaly or macrocephaly, stroke, intestinal atresia/stenosis, hepatomegaly, splenomegaly, or urogenital anomalies)
●Dysmorphic features
●Failure to thrive or growth abnormalities (short or tall stature)
●Abnormal tone (eg, hypotonia, spasticity, dystonia)
Although diagnostic tests for chromosome abnormalities and single gene disorders have the highest yield when these findings are present, testing has a diagnostic yield even if such features are absent. The diagnostic yields of different tests or testing approaches are summarized in the table (table 2); the reported diagnostic yields are estimated based on meta-analysis of different patient groups rather than representative population-based samples [46].
Chromosomal microarray analysis — CMA is preferred over G-banded karyotype analysis or subtelomeric fluorescence in situ hybridization (FISH) as the first-line genetic test for unexplained ID due to its higher sensitivity and thus greater diagnostic yield (table 2) [2,23,63-66]. CMA is also known as molecular karyotyping, microarray-based genomic copy-number analysis, or array-based comparative genomic hybridization (aCGH). (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Array comparative genomic hybridization'.)
The use of CMA leads to a genetic diagnosis in 15 to 20 percent of patients with unexplained ID (table 2). The higher yield of CMA compared with G-banded karyotype analysis or FISH is primarily because of its sensitivity for submicroscopic copy-number variations (ie, deletions and duplications) [67]. In a meta-analysis of 33 studies of patients with ID, autism spectrum disorder, or multiple congenital anomalies, the average diagnostic yield of CMA was 12 percent [23]. In another study of more than 35,000 patients with ID, CMA detected a pathogenic abnormality in nearly 19 percent of patients [68].
CMA does not detect point mutations (sequence variants) responsible for single-gene disorders. In addition, CMA will not identify balanced translocations, such as translocations or inversions and may not detect low-level mosaicism, but these are relatively infrequent causes of abnormal phenotypes in this population.
Clinicians should be aware that there are different platforms for CMA studies. Oligonucleotide-based arrays provide a superb means of detecting DNA copy-number changes, including single exon deletions [69,70]. There are a large number of designs of CMA with different levels of resolution (from approximately 1 Mb to several kb). The arrays might be whole-genome arrays, designed to cover the entire genome, or targeted arrays, which target known disease-causing regions.
Single nucleotide polymorphism (SNP) arrays can detect copy-number changes, as well as long contiguous stretches of copy-number neutral regions of absence of heterozygosity, that can be associated with uniparental disomy or parental consanguinity. Both of these findings increase the risk for autosomal recessive conditions. In addition, SNP arrays detect triploidy, low-level mosaicism, and chimerism [71]. Combined oligonucleotide/SNP arrays are also available to pool the advantages of each method [72].
Deciphering variants of uncertain clinical significance may be challenging. Interpretation of a CMA result requires expert review to determine whether a copy-number variant is clinically significant. In some cases, testing of the patient's parents is necessary to fully assess the clinical significance of a result to enable appropriate genetic counseling [23,73]. Incomplete penetrance and variable expressivity are frequently observed for several disorders associated with genomic microdeletions and microduplications. Carrier parents may be completely healthy for some of these disorders, such as 15q13.3 deletion, 1q21.1 deletion, and NRXN1 deletion.
If the CMA testing result is normal or yields a known benign variant, then further evaluation using specific tests may be considered, as recommended in a consensus statement [23]. If CMA fails to find a cause of ID, whole exome sequencing (WES) can be applied to identify causative mutations. (See 'Whole exome sequencing' below.)
Testing for fragile X syndrome — Fragile X syndrome is caused by an abnormal expansion mutation of a CGG triplet repeat in the FMR1 gene (typically >200) and is the most prevalent form of inherited ID [74]. Most affected males and approximately one-half of females with a full fragile X mutation have ID. Males generally have moderate to severe ID and may not have the characteristic appearance; affected females tend to have mild ID. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)
Selection criteria for fragile X testing vary among authorities. Most experts recommend fragile X testing for all children in the following groups (table 2) [23,74]:
●Males and females with ID and clinical features suggesting fragile X syndrome (eg, macrocephaly, large ears, enlarged testes after puberty in males, perseverative speech, and poor eye contact)
●Males and females with unexplained ID or developmental delay and a family history of ID
In addition, many authorities suggest fragile X testing for all children with the following characteristics:
●Males and females with ID whose initial microarray testing is normal or benign [23]
●Males and females with unexplained ID (because of a 1 to 3 percent diagnostic yield [46])
●Males and females with unexplained autism [74,75]
●Males and females with borderline ID [74]
In many institutions, fragile X testing is done concurrently with CMA for the evaluation of ID in children.
Karyotype analysis — G-banded karyotype analysis should be reserved for the following circumstances [23]:
●A common aneuploidy is suspected based on clinical findings (eg, Down syndrome, trisomy 18, or a sex chromosome aneuploidy). (See 'Testing for specific disorders' above and "Down syndrome: Clinical features and diagnosis" and "Congenital cytogenetic abnormalities", section on 'Numeric abnormalities' and "Clinical features, diagnosis, and management of Klinefelter syndrome".)
●There is concern for balanced translocation (eg, maternal history of frequent miscarriages, or a family history of translocation).
●CMA is unavailable.
G-banded karyotype analysis detects major structural abnormalities and will not detect smaller regions of DNA gain or loss. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Chromosomal analysis'.)
Metabolic testing — ID is a clinical feature of some IEM. Most affected children have other manifestations of metabolic disease, such as episodic decompensation, seizures, developmental regression, failure to thrive, or abnormal neurologic exam. In addition, screening programs in the United States identify many newborns with IEM.
For children with unexplained ID, the yield of routine metabolic investigations is low, ranging from 0.8 to 3 percent (table 2), but the potential for improved outcomes after diagnosis and treatment is high [2]. These laboratory tests are appropriate for children with ID and clinical features suggestive of metabolic disease, as outlined above.
To perform metabolic screening, concentrations of plasma amino acids, urine organic acids, serum ammonia, and lactate are most often measured; very long-chain fatty acids and carnitine may also be measured on blood samples [23]. Electrolytes are measured to detect acidosis. If further metabolic testing is performed and guided by a specialist, the diagnostic yield increases to at least 3 percent, particularly in children with suggestive clinical features [46]. Other possible tests include urine and plasma creatine and guanidinoacetate (for creatine synthesis and transport disorders), blood homocysteine and transferrin electrophoresis, urine glycosaminoglycans, urine purines and pyrimidines, and oligosaccharides [2,46,59]. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Developmental delay'.)
Whole exome sequencing — WES should be considered for patients with moderate to severe ID in whom other standard tests (including CMA) have failed to identify the cause (algorithm 1). The diagnostic yield of WES in this setting is approximately 16 to 33 percent [17,22,32,34,35,76]. The diagnostic yield is likely lower in patients with mild ID without additional findings and the role of WES testing in this population is not defined.
WES testing should be performed with consultation of a clinical geneticist and should include appropriate pretest counseling to discuss the risk of incidental findings unrelated to the child's ID that may be medically actionable (eg, BRCA1 or BRCA2 mutation) [77]. Incidental findings can be minimized if a focused analysis is conducted. (See 'Referral and follow-up' below and "Secondary findings from genetic testing".)
Due to the falling costs of sequencing and its high diagnostic yield, WES is rapidly becoming a clinical tool for the evaluation of ID, especially at specialty centers [36]. Adoption of WES testing into the diagnostic process will depend on its cost, availability, access to expert interpretation, and the allocation of resources within each health care setting [78]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Practical issues'.)
Fluorescence in situ hybridization (FISH) — Chromosomal rearrangements in the gene-rich subtelomeric region are identified in approximately 4 to 6 percent of children with ID [79]. Molecular screening using FISH of subtelomeric probes was used widely in the past to identify these abnormalities; however, CMA has replaced FISH as the test of choice, since the majority of diagnostic CMA arrays offer dense coverage of subtelomeric regions (table 2). FISH may still be substituted if array diagnosis is not available or if a specific telomeric disorder (eg, DiGeorge syndrome, Cri-du-chat syndrome) is strongly suspected clinically. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Fluorescence in situ hybridization' and "Congenital cytogenetic abnormalities", section on '5p deletion syndrome (cri-du-chat syndrome)' and "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)
Other tests
Lead screening — Blood lead testing should be performed if the child has not had prior lead screening. In addition, lead screening should be performed if any of the following risk factors for lead exposure are present:
●Persistent mouthing behavior and pica
●Living in a house or child care facility built before 1950
●Recent immigration or home renovation
●Ethnic remedies, and some parental occupations (smelting, soldering, and auto body repair)
Although lead toxicity is an uncommon cause of ID in the United States, children with ID are at increased risk for lead exposure, partly because they progress slower and spend longer in stages where mouthing behavior is common. In one report, blood lead levels >10 mcg/dL occurred in a greater proportion of children with behavioral and/or developmental problems than in controls (12 versus 0.7 percent) [80].
Lead is the most common environmental neurotoxin. Lead exposure can harm cognitive function at any level [81]. Childhood lead poisoning is discussed in greater detail separately. (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Screening tests in children and adolescents", section on 'Lead poisoning'.)
Neuroimaging — We suggest neuroimaging be obtained (preferably with magnetic resonance imaging [MRI]) if there are concerning features in the history (eg, seizures, progressive or degenerative neurologic symptoms) or abnormal findings on physical examination (eg, microcephaly, macrocephaly, focal neurologic deficits). Consultation with a pediatric neurologist may be warranted in these cases. This approach is consistent with recommendations of the American Academy of Neurology, the Child Neurology Society, and the American Academy of Pediatrics [2,9].
MRI is the preferred imaging modality; however, computed tomography may be acceptable if MRI is not available. Potential radiation exposure and risk of sedation should be considered as part of informed decision-making.
Abnormal findings on neuroimaging are seen in approximately 30 percent of children with GDD/ID; however, most abnormalities are nonspecific, and often do not lead to a specific diagnosis or alter clinical management [2,60,82,83]. Common findings include CNS malformations, white matter abnormalities, and cerebral atrophy. The yield is higher among children with specific physical features such as microcephaly, epilepsy, or abnormal motor signs [8,83].
REFERRAL AND FOLLOW-UP — Referral to a pediatric geneticist is valuable for many children with ID, especially those with moderate to severe ID who remain undiagnosed despite appropriate investigation. The consultation may yield a definitive diagnosis and can facilitate genetic counseling for the family and appropriate management of the patient.
Children with syndromic features and/or abnormal results of initial genetic testing (which may include chromosomal microarray analysis, fragile X testing, G-band karyotype, and/or metabolic studies) should promptly be referred to a clinical geneticist for further evaluation and counseling. In addition, clinicians should consult geneticists early in the evaluation of unexplained ID, particularly if the initial work up is negative.
Depending on the cost and the available resources, clinical geneticists can recommend whole exome sequencing (WES) after appropriate pretest counseling. All families should undergo pretest counseling with a formal informed consent before WES is undertaken [77]. In a child with suspected genetic disorder and a nondiagnostic WES study, re-evaluation is recommended every few years, in view of the expanding scientific advances concerning novel genetic disorders of ID. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)
SUMMARY AND RECOMMENDATIONS
●Intellectual disability (ID) is a neurodevelopmental disorder with multiple etiologies that is characterized by deficits in intellectual and adaptive functioning that affect at least one adaptive domain (conceptual, social, and/or practical) with varying severity (table 1A-B). In the general population, the prevalence of ID is approximately 1 percent. ID is mild in approximately 85 percent of affected individuals. (See 'Introduction' above and 'Epidemiology' above and "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis".)
●A genetic cause can be identified in >50 percent of cases of ID in populations referred for specialty evaluation. Down syndrome is the single most common genetic cause of ID. X-linked disorders (including fragile X syndrome) account for approximately 5 to 10 percent of ID in males. De novo dominant mutations are an important cause of severe ID. (See 'Genetic causes' above.)
●Nongenetic prenatal causes of ID include congenital infections, and teratogens such as alcohol, lead, and valproate. Perinatal abnormalities account for up to 5 percent of ID and include preterm birth, hypoxia, infection, trauma, and intracranial hemorrhage. Postnatal and acquired causes of ID include accidental or nonaccidental trauma, central nervous system (CNS) hemorrhage, congenital hypothyroidism, hypoxia (eg, near-drowning), environmental toxins, psychosocial deprivation, malnutrition, intracranial infection, and CNS malignancy. (See 'Environmental causes' above.)
●Selection and sequence of diagnostic tests in children with ID is guided by individual patient characteristics and the availability of specific tests. The evaluation begins with a detailed medical history (including review of newborn screening results), family history, and thorough physical examination (including neurologic examination and evaluation for dysmorphic features). (See 'Approach to diagnostic testing' above.)
●Children with ID, particularly those with moderate to severe ID, should be offered referral for a genetics consultation. Consultation may yield a definitive diagnosis and facilitate counseling and condition-specific management and support. (See 'Referral and follow-up' above.)
●In children with features suggestive of a specific diagnosis, the initial evaluation involves testing for the specific syndrome or disorder (table 3). (See 'Testing for specific disorders' above.)
●For children with unexplained ID (ie, those without features suggestive of a specific diagnosis and those with negative results of specific tests), we suggest the following testing for genetic and metabolic disorders (algorithm 1):
•Chromosomal microarray (CMA) is the first-line genetic test for unexplained ID and detects a cause in 15 to 20 percent of the cases of ID (table 2). Abnormalities that can be detected by CMA include submicroscopic deletions and duplications. If CMA is not available, then G-banded karyotype and fluorescence in situ hybridization testing may be applied instead. (See 'Chromosomal microarray analysis' above.)
•For patients with features that suggest the possibility of a balanced translocation in the family (eg, maternal history of frequent miscarriages or a family history of chromosomal abnormalities), G-banded karyotyping should be performed either before or in addition to CMA. (See 'Karyotype analysis' above.)
•If the CMA is normal or benign, fragile X testing should be performed (if not already done). (See 'Testing for fragile X syndrome' above.)
•Blood lead testing should be performed if the child has not had prior lead screening and/or risk factors for exposure are present (eg, persistent mouthing behavior, pica, living in a house or child care facility built before 1950, recent immigration or home renovation, ethnic remedies, and some parental occupations [smelting, soldering, and auto body repair]). (See 'Lead screening' above.)
•Neuroimaging should be performed if there are concerning features in the history (eg, seizures, progressive or degenerative neurologic symptoms) or abnormal findings on physical examination (eg, microcephaly, macrocephaly, focal neurologic deficits). Magnetic resonance imaging is the preferred imaging modality. (See 'Neuroimaging' above.)
•If the above testing is negative, genetics consultation can guide further evaluation, which may include metabolic testing (if not done previously) and/or whole exome sequencing (depending on availability). (See 'Metabolic testing' above and 'Whole exome sequencing' above.)
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