August 2025
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. ID affects approximately 1 to 2 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.
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 and are described in greater detail in a separate topic review (see "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis"):
●Global developmental delay (GDD) – GDD is the preferred term to describe intellectual and adaptive impairment in infants and young children <5 years old who fail to meet expected developmental milestones in multiple areas of functioning. GDD may be used as a provisional diagnosis until comprehensive standardized testing can be accurately and reliably completed. Not all children with GDD meet criteria for ID as they grow older.
●Intellectual disability (ID) – ID is a neurodevelopmental disorder that begins in childhood. It is characterized by limitations in both intelligence and adaptive skills, affecting at least one (but typically all) of the three adaptive domains (conceptual, social, and practical (table 1)). The extent of adaptive impairment is key to defining ID and its severity (table 2).
●Syndromic versus nonsyndromic ID – ID may be further categorized as syndromic or nonsyndromic ID. The term syndromic ID is applied when intellectual and adaptive impairment occurs with other physical or comorbid symptoms that may be recognizable as a syndrome (eg, Down syndrome, fragile X syndrome). When ID occurs without features of a possible recognizable syndrome, the term nonsyndromic ID is used.
EPIDEMIOLOGY
Prevalence — Reported prevalence rates of ID vary somewhat due to differences in study design, diagnostic criteria, severity, and the population studied. In the general population, the prevalence of ID is approximately 1 to 2 percent [1-4]. ID is mild in approximately 85 percent of affected individuals.
The prevalence of global developmental delay (GDD) is estimated to be approximately 1 to 3 percent [1]. GDD does not necessarily predict later ID, although there is a strong correlation.
In low- and middle-income countries, reported prevalence rates of GDD and ID are higher, ranging from 4 to 10 percent [1,5-7].
Approximately 20 to 30 percent more males are diagnosed with ID compared with females [8]; however, the sex difference diminishes with more severe ID.
The prevalence of mild ID varies depending on the prevalence of risk factors and causes of ID within the population (eg, preterm birth; perinatal asphyxia; congenital infections; and maternal exposure to alcohol, toxins, and certain medications). (See 'Risk factors' below and 'Causes' below.)
Risk factors — Numerous risk factors for ID have been identified, though they differ somewhat depending on the severity of ID.
Sociodemographic factors that are associated with increased risk of mild ID include [9-12]:
●Low level of maternal education [9]
●Poverty [10,11]
●Advanced maternal age [9,12]
●Advanced paternal age (likely attributed to de novo sequence variants that accumulate with increasing paternal age) [13]
●Preterm birth and/or low birth weight [14]
CAUSES —
The causes of ID are extensive and include conditions that interfere with brain development and functioning. Among the known causes of ID, most are genetic abnormalities. Nongenetic causes (eg, prenatal exposures, postnatal insults) are also important to consider.
Genetic causes — As genetic testing techniques have advanced, the identification of genetic causes of ID has increased dramatically. A specific genetic cause can be identified in >50 percent of individuals with ID referred for evaluation [15-18]. Genetic disorders can cause ID as an isolated finding (nonsyndromic ID) or in combination with other neurologic abnormalities such as epilepsy, structural brain defects, and/or other congenital anomalies (syndromic ID).
The increasing use of next-generation DNA sequencing (NGS) techniques (ie, NGS-based gene panel testing, exome sequencing, and genome sequencing) has uncovered many more genes involved in both syndromic and nonsyndromic forms of ID [17,18]. (See 'Exome or genome sequencing' below and "Next-generation DNA sequencing (NGS): Principles and clinical applications".)
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)
The following sections summarize some important genetic causes of ID, though the lists within each section are not comprehensive.
Chromosomal abnormalities — Chromosomal aberrations are common causes of ID. Karyotype abnormalities have been reported in 5 to 6 percent of individuals with ID [19,20]. Nearly all unbalanced chromosomal rearrangements that are cytogenetically visible can cause ID (with the exception of sex chromosome abnormalities). (See 'Clinical suspicion for a specific disorder' below and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Chromosomal analysis'.)
●Down syndrome – Down syndrome, or trisomy 21, is the most common known genetic cause of ID. (See "Down syndrome: Clinical features and diagnosis".)
●Deletion, microdeletion, and duplication syndromes – Disorders resulting from deletions, microdeletions, or duplications of chromosomal material have been recognized as a frequent cause of ID. Many of these chromosomal abnormalities, also called DNA copy number variations (CNVs), are below the resolution threshold of G-banded chromosome analysis, and therefore CMA or fluorescence in situ hybridization (FISH) are required for detection. CNVs are identified in approximately 15 to 20 percent of individuals undergoing evaluation for unexplained ID [21,22].
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) (see "Microdeletion syndromes (chromosomes 1 to 11)", section on '7q11.23 deletion syndrome (Williams syndrome)')
•17p11.2 deletion syndrome (Smith-Magenis syndrome) (see "Microdeletion syndromes (chromosomes 12 to 22)", section on '17p11.2 deletion including RAI1 (Smith-Magenis syndrome)')
•15q11-13 maternal and paternal deletion syndromes (Angelman and Prader-Willi syndromes) (see "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion (Angelman syndrome)' and "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 paternal deletion (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 [23,24]. Numerous genes are known to be associated with autosomal dominant ID, and the list continues to evolve [25]. Novel pathogenic genetic variants are identified every year using next-generation sequencing techniques (exome/genome sequencing) [26].
"Trio" exome or genome 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 [27]. Severe ID could be caused by de novo variants in approximately 35 to 45 percent of affected children [15,24]. (See 'Exome or genome 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 ADNP, ANKRD11, ARID1B, CACNA1A, CDK13, CHD8, CREBBP, DYRK1A, EHMT1, EP300, FOXP1, KANSL1, KAT6A, KAT6B, KMT2A, KMT2D, MED13L, NF1, NSD1, PURA, RNU4-2, SATB2, SCN1A, SCN2A, SHANK3, STXBP1, SYNGAP1, TCF4, TSC1, and TSC2, [15,17,28-31]. Genetic variants in these genes often cause other comorbidities such as epilepsy, craniofacial dysmorphism, and/or congenital anomalies.
ReNU syndrome, which is caused by de novo variants in the noncoding gene RNU4-2, is among the most common monogenic causes of ID [32,33]. Although the presentation is variable, this disorder should be considered in a child who presents with ID in association with microcephaly, hypotonia, and full cheeks. Genome sequencing is the only currently available method to identify this disorder, although it will likely be included in targeted gene panels for ID given its relatively high prevalence.
Autosomal recessive inheritance — Autosomal recessive disorders occur particularly in consanguineous families [34], but they can occur in families without consanguinity.
●Inborn errors of metabolism (IEM) – Metabolic disorders are often associated with ID and may be causative in up to 3 percent of patients with unexplained ID [35]. Newborn screening efforts have been pivotal in the early diagnosis and treatment of affected children. Early detection of treatable IEM enables specific intervention, functional improvement, or stabilization. Although children with IEM may present with ID alone, most have additional features (eg, episodic decompensation, poor growth, seizures, developmental regression, abnormal findings on neurologic examination, and/or hepatomegaly) [34]. (See 'Metabolic testing' below and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Developmental delay'.)
●Other autosomal recessive disorders – Other examples of recessive disorders causing ID include disease causing variants in ADAT3, ASPM, CC2D1A, CEP290, CRBN, CRADD, GRIK2, MAN1B1, MED23, METTL23, NSUN2, POLG, PRSS12, SLC6A17, ST3GAL3, TAF2, TANGO2, TECR, TRAPPC9, TUSC3, and VPS13B [36-40]. These disorders are increasingly identified by NGS. (See 'Exome or genome 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 [41-43]. 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 [42]. 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 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 variants 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 'Clinical suspicion for a specific disorder' 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 duplication (or triplication) of the MECP2 gene and is a cause of severe to profound ID in males [44]. Females with MECP2 duplication are usually asymptomatic, although mild to severe cognitive impairment has been described [45,46]. MECP2 duplications account for approximately 1 percent of unexplained X-linked ID [44]. 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. Of note, MECP2 sequencing by itself will not detect duplications. This disorder can be diagnosed with CMA and NGS-based gene panels. (See 'First-line genetic tests' below.)
•DDX3X variants – Pathologic variants in DDX3X are responsible for 1 to 3 percent of ID cases in females; affected male individuals have also been reported [47]. 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) [47,48].
●Other X-linked disorders – X-linked creatine transporter deficiency, caused by pathogenic variants in SLC6A8, is characterized by mild to severe ID in males, with speech and motor delay, behavioral abnormalities, and seizures [49]. 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 ABCD1, ARX, ATP7A, ATRX, CDKL5, DMD, GLRA2, KDM5C, L1CAM, MED12, NONO, OCRL, PQBP1, RSK2, TCEAL1, USP9X, and WNK3 [50,51].
Pelizaeus-Merzbacher disease is a rare X-linked hypomyelinating disorder caused by duplication or point mutation of the PLP1 gene [52,53]. It is characterized by progressive motor and intellectual deterioration in males. The diagnosis can be established with brain magnetic resonance imaging (MRI) and PLP1 sequencing and duplication testing (with either single gene testing or a gene panel). CMA will detect PLP1 duplication but not sequencing variants.
Mitochondrial disorders — Mitochondrial disorders are a heterogeneous group of diseases that are often associated with ID as well as other neuromuscular, cardiopulmonary, ophthalmologic, or kidney 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) [54]. (See "Mitochondrial myopathies: Clinical features and diagnosis".)
Imprinting disorders — These disorders result from dysregulation of the normal expression of parent-specific imprinted genes due to either deletion, uniparental disomy, or an imprinting defect. An imprinted locus at 15q11–q13 is responsible for Angelman syndrome and Prader-Willi syndrome, both of which represent syndromic forms of ID [55,56]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion (Angelman syndrome)' and "Prader-Willi syndrome: Clinical features and diagnosis".)
Nongenetic causes — ID resulting from nongenetic causes may be due to prenatal, perinatal, and/or postnatal exposures [57]:
Prenatal causes — Important nongenetic prenatal causes of ID include:
●Congenital infections (table 3). (See "Overview of TORCH infections".)
●Prenatal exposure to toxins or teratogens (eg, alcohol or other substance use, lead, mercury, phenytoin, valproate, radiation exposure). (See "Fetal alcohol spectrum disorder: Clinical features and diagnosis" and "Substance use during pregnancy: Overview of selected drugs" and "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Effects of ASMs on the fetus and child'.)
●Nutritional deficiencies during pregnancy (eg, iron deficiency anemia, vitamin B12 deficiency) [58]. These issues can be remedied if detected early in pregnancy. (See "Anemia in pregnancy", section on 'Supporting evidence for adverse outcomes associated with anemia'.)
●Maternal complications and conditions during pregnancy (eg, diabetes, epilepsy, preeclampsia) [12,59]. (See "Infants of mothers with diabetes (IMD)", section on 'Neurodevelopmental outcome'.)
Perinatal causes — Perinatal abnormalities that may cause or contribute to ID include:
●Preterm birth (see "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors")
●Perinatal asphyxia (see "Perinatal asphyxia in term and late preterm infants")
●Intracranial hemorrhage (see "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Long-term neurodevelopmental outcomes')
●Infection (see "Neonatal bacterial sepsis: Treatment, prevention, and outcome in neonates born at less than 35 weeks gestation", section on 'Morbidity')
Postnatal causes — Postnatal and acquired causes of ID may be easier to identify, as they typically occur in a child whose development was previously on track. Etiologies include:
●Direct central nervous system (CNS) insult due to:
•Traumatic brain injury (accidental or nonaccidental) (see "Severe traumatic brain injury (TBI) in children: Initial evaluation and management", section on 'Outcomes' and "Physical child abuse: Recognition")
•Infection (eg, meningitis, encephalitis) (see "Bacterial meningitis in children: Neurologic complications", section on 'Developmental delay and intellectual disability' and "Acute viral encephalitis in children: Treatment and prevention", section on 'Neurologic sequelae')
•Hemorrhage (see "Hemorrhagic stroke in children", section on 'Neurologic outcome')
•Hypoxic insult (eg, near-drowning) (see "Drowning (submersion injuries)", section on 'Outcome')
•Tumor (see "Overview of the management of central nervous system tumors in children", section on 'Neurocognitive effects')
●Exposure to environmental toxins (eg, lead). (See "Childhood lead poisoning: Clinical manifestations and diagnosis", section on 'Neurologic'.)
●Psychosocial deprivation.
●Malnutrition. (See "Malnutrition in children in resource-limited settings: Clinical assessment".)
●Hypothyroidism (congenital or acquired) – If unrecognized and untreated, congenital hypothyroidism may cause intellectual impairment; where newborn screening is available, early screening and treatment have mostly eliminated ID due to congenital hypothyroidism. (See "Clinical features and detection of congenital hypothyroidism" and "Acquired hypothyroidism in childhood and adolescence", section on 'Clinical manifestations'.)
Multifactorial etiology — Some children with ID who remain undiagnosed after comprehensive genetic testing 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 would be expected to have greater impact.
APPROACH TO ETIOLOGIC EVALUATION —
The selection and sequence of diagnostic tests to identify a cause in children with ID is guided by a detailed history (including three-generation family pedigree), thorough physical examination (including neurologic examination and evaluation for dysmorphic features), and the availability and cost of the specific tests [60]. A collaborative approach that includes parent/caregiver participation in the child's evaluation is important. Tests may vary across clinical settings and different regions, especially where newborn screening programs and access to next-generation sequencing differ.
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 spectrum disorder (ASD), 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 to provide more information to the family about the prognosis, comorbidities, anticipated 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. 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.
Clinical suspicion for a specific disorder — Children with dysmorphic features or other characteristics that suggest a particular syndrome or disorder should undergo targeted testing to confirm or rule out that specific disorder (table 4).
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 4).
●Down syndrome or other common aneuploidy – For children with clinical features suggesting Down syndrome or other common aneuploidy (eg, 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. However, the distinctive clinical features are often absent or subtle in young children with fragile X syndrome. Males and females with unexplained ID and a family history of ID or ASD should be evaluated for the syndrome. (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".)
●Angelman and Prader-Willi syndromes – DNA methylation analysis is the preferred initial molecular testing method for evaluating individuals with suspected Angelman syndrome or Prader-Willi syndrome (PWS). PWS may be suspected based upon characteristic clinical findings in infancy (severe hypotonia, poor feeding, cryptorchidism) or in childhood (ID associated with hyperphagia, obesity, short stature, and hypogonadism). Angelman syndrome is characterized by severe ID; microcephaly; hypermotoric behavior with ataxia and unsteady gait; a happy demeanor with frequent laughter, emotional lability, and easy excitability; and a fascination with water. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion (Angelman syndrome)' and "Prader-Willi syndrome: Clinical features and diagnosis", section on 'Diagnosis'.)
●Inborn errors of metabolism (IEM) – ID is a clinical feature of some IEM. Most affected children have other manifestations of metabolic disease, such as episodic decompensation, seizures, developmental regression, growth failure, abnormal neurologic examination, 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 [61,62]. The presence of these features increases the likelihood of identification of a disorder compared with nonselective screening [63]. (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 GDD or ID associated with proximal muscle weakness, measuring serum creatine kinase (CK) can be a useful initial test in the diagnostic evaluation to assess for Duchenne muscular dystrophy. If CK is elevated, specific genetic testing can be performed. Early identification of this disorder enables early intervention and family counseling. Becker muscular dystrophy may also be associated with ID, but the muscular disease tends to be milder. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)
Children with unexplained ID — If no specific disorder is clinically suspected or if initial testing for specific disorders is nondiagnostic, then broader genetic testing for unexplained ID should be offered (algorithm 1) [18,21,60].
Rationale for genetic testing — Genetic testing should be offered to individuals with unexplained ID because testing 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. Clinicians should engage in shared decision-making with parents/caregivers, including comprehensive pretest counseling, especially before performing genetic sequencing tests.
The likelihood of identifying a genetic disorder is increased when any of the following features are present (particularly in combination):
●Severe ID.
●Dysmorphic features.
●Multisystem involvement or/multiple congenital anomalies (eg, sensorineural hearing loss, visual problems, congenital heart defects, skeletal abnormalities, endocrine problems, central nervous system [CNS] malformations, seizures, microcephaly or macrocephaly, urogenital anomalies, and other birth defects).
●Abnormal growth (growth failure, overgrowth, short or tall stature).
●Abnormal tone (eg, hypotonia, spasticity, dystonia).
●Family history of consanguinity.
●Family history of ID or other neurodevelopmental disorders.
●Maternal history of multiple miscarriages or family history of infant deaths.
Although genetic testing has the highest yield when these findings are present, testing has a reasonably high diagnostic yield even if such features are absent. Thus, genetic testing should be offered to all children with unexplained ID. The diagnostic yields of different tests or testing approaches are summarized in the table (table 5) and discussed in the sections below.
First-line genetic tests — First-line genetic tests for evaluating unexplained ID include any of the following (algorithm 1) [18,21,60]:
●Exome sequencing (see 'Exome or genome sequencing' below)
●Genome sequencing (see 'Exome or genome sequencing' below)
●Chromosomal microarray analysis (CMA) (see 'Chromosomal microarray analysis' below)
The choice depends upon test availability, institutional preference, cost, insurance limitations, and parent/caregiver agreement. Exome or genome sequencing are often preferred over CMA given their higher diagnostic yield. However, their widespread adoption may be constrained by factors such as cost and insurance coverage limitations.
The 2021 guidelines of the American College of Medical Genetics endorse either exome/genome sequencing or CMA as acceptable first-line tests [18].
Exome or genome sequencing — The advances of genetic sequencing testing have improved diagnostic yields for exome and genome sequencing in the evaluation of unexplained ID (table 5) [64].
●Exome sequencing – The diagnostic yield for exome sequencing is approximately 30 to 40 percent for individuals with unexplained ID of any severity and approximately 55 percent for those with moderate to severe ID [27,65,66]. Trio-based exome sequencing examines each parent as well as the child, identifying candidate genes and improving diagnostic yield [67,68]. A limitation of exome sequencing is that it does not identify triplet repeat disorders (fragile X) or methylation disorders (Prader-Willi or Angelman syndromes) [18]. Standard exome sequencing is generally limited in detecting copy number variations (CNVs; ie, deletions and duplications). However, newer analysis tools are available that can identify CNVs from the exome data.
●Genome sequencing – Genome sequencing has a diagnostic yield of approximately 35 to 45 percent or as high as 60 percent, depending on the population studied [18,69]. Advantages of genome sequencing are that it can potentially identify CNVs and triplet repeat disorders such as fragile X.
The diagnostic yields of exome/genome sequencing are considerably higher than that of CMA, although at higher cost [70-72]. Thus, practice has shifted to incorporate these tools earlier in the diagnostic evaluation, particularly in specialist settings. The application of these tests depends upon multiple factors, including cost, availability, access to expert interpretation, and the allocation of resources within each health care setting [73]. Exome/genome sequencing can be used as first-line genetic tests for unexplained ID or as second-line tests after CMA and/or targeted testing have failed to find the cause, provided parents/caregivers agree [18].
Ideally, sequencing tests should be performed with consultation of a clinical geneticist who can prepare the family/caregivers for the risk of incidental findings unrelated to the child's ID that may be medically actionable (eg, BRCA1 or BRCA2 pathogenic variants) [74]. Incidental findings can be minimized if a focused analysis is conducted. Pretest counseling with parent/caregiver consent is important prior to genetic testing, particularly before performing sequencing tests. Counseling should address all aspects pertinent to the evaluation and should occur in the context of shared decision-making [75]. (See 'Referral and follow-up' below and "Secondary findings from genetic testing" and "Next-generation DNA sequencing (NGS): Principles and clinical applications".)
If exome or genome sequencing is nondiagnostic, we suggest performing re-analysis in a few years since new disease associated genes may be identified over time [76]. In addition, it is important to ensure that the possibility of fragile X has not been overlooked. (See 'Testing for fragile X syndrome' below.)
Chromosomal microarray analysis — 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 diagnostic yield of CMA in individuals with unexplained ID is approximately 15 to 20 percent (table 5) [21,22]. CMA is preferred over G-banded karyotype analysis or subtelomeric fluorescence in situ hybridization (FISH) for evaluation of unexplained ID due to its higher sensitivity and greater diagnostic yield [21,60,77-80]. The higher yield of CMA compared with G-banded karyotype analysis or FISH is primarily because of its sensitivity for submicroscopic CNVs (ie, deletions and duplications) [81]. CNVs detected by CMA are thus important contributors of ID and should be considered early in the evaluation.
CMA does not detect any of the following:
●Point mutations (sequence variants) responsible for single-gene disorders. Thus, if CMA is nondiagnostic, exome or genome sequencing can be applied to identify causative mutations since these tests have higher diagnostic yield compared with CMA. (See 'Exome or genome sequencing' above.)
●Trinucleotide repeat expansions that are responsible for fragile X syndrome. Separate testing for fragile X should be performed if there are suggestive clinical features or a family history of ID. (See 'Testing for fragile X syndrome' below.)
●Balanced translocations, such as translocations or inversions and low-level mosaicism. These are relatively infrequent causes of ID.
Clinicians should be aware that there are different platforms for CMA studies. Oligonucleotide-based arrays detect DNA copy-number changes, including single exon deletions [82,83]. 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 CNVs, 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 can detect triploidy, low-level mosaicism, and chimerism [84]. Combined oligonucleotide/SNP arrays are also available to pool the advantages of each method [85].
Deciphering variants of uncertain clinical significance may be challenging. Interpretation of a CMA result requires expertise to determine whether a CNV is clinically significant. This is usually best accomplished in consultation with geneticists, genetic counselors, or other neurodevelopmental specialists with training and expertise in interpreting genetic testing results. For variants of uncertain significance, testing of the patient's parents is usually recommended to fully assess the clinical significance of the genetic change and to enable appropriate genetic counseling [21,86]. Incomplete penetrance and variable expressivity are observed for several disorders associated with genomic microdeletions and microduplications. Carrier parents may be apparently healthy for some of these disorders, such as 15q13.3 deletion, 1q21.1 deletion, 16p11.2 deletion, and 22q11.2 duplication. (See 'Referral and follow-up' below.)
Other genetic tests
Testing for fragile X syndrome — Fragile X syndrome is caused by an abnormal expansion mutation of a CGG triplet repeat in the FMR1 gene (>200) and is the most prevalent form of inherited ID [87]. Most affected males and approximately one-half of females with a full fragile X mutation have ID. Males generally have moderate to severe ID with or without the characteristic appearance; affected females tend to have mild ID with little to no physical findings.
CMA and exome sequencing do not detect the trinucleotide repeat expansions diagnostic of fragile X syndrome, whereas genome sequencing can identify triplet repeat disorders. In most cases, the diagnosis is made by fragile X DNA analysis (also called fragile X CGG repeat analysis). (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)
Selection criteria for fragile X testing vary. Most experts recommend fragile X testing in either of the following scenarios (table 5) [21,87]:
●Males with ID and clinical features suggesting fragile X syndrome (eg, macrocephaly, large ears, enlarged testes after puberty, perseverative speech, gaze aversion, social difficulties, hyperactivity, impulsivity, anxiety, and visual-spatial or mathematics deficits).
●Males and females with unexplained ID or developmental delay and a family history of ID or ASD.
In our practice, we perform fragile X testing selectively based upon the above criteria given the low diagnostic yield of routine testing in individuals without suggestive clinical features or positive family history (table 5) [88-91]. However, practice varies, and other centers may routinely perform fragile X testing concurrently with CMA in children undergoing evaluation for unexplained ID. When using a selective approach, clinicians should be aware that suggestive features are often absent or subtle in young children with fragile X syndrome.
Karyotype analysis — 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'.)
For children undergoing evaluation for unexplained ID, use of G-banded karyotype analysis is limited to the following circumstances [21]:
●There is concern for balanced translocation in a parent (eg, maternal history of frequent miscarriages, or a family history of translocation)
●CMA and exome/genome sequencing are unavailable
G-banded karyotype analysis may be used as a first-line test in children with clinical findings suggestive of a common aneuploidy (eg, Down syndrome or a sex chromosome aneuploidy), as discussed above. (See 'Clinical suspicion for a specific disorder' above.)
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 examination. In addition, screening programs in the United States and other parts of the world identify many newborns with IEM. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Newborn screening'.)
For children undergoing evaluation for unexplained ID, the role of routine metabolic testing is uncertain. We typically perform this testing only in the following circumstances [60]:
●When there is clinical concern for an IEM based upon associated clinical findings (eg, episodic decompensation, seizures, developmental regression, growth failure, abnormal neurologic exam). (See 'Clinical suspicion for a specific disorder' above.)
●If CMA and exome/genome sequencing are nondiagnostic, unavailable, or not chosen by the family/caregivers. Since many IEM disorders are treatable and there is potential for improved outcomes with timely diagnosis and early treatment, metabolic testing may be pursued if exome/genome sequencing is not available or is nondiagnostic [60,92].
●To resolve variants of uncertain significance detected on exome/genome sequencing. Global metabolomics can sometimes serve as a useful adjunct to exome/genome sequencing for interpretation of variants of uncertain significance and to help confirm IEMs [93-95].
For children with unexplained ID, the yield of routine metabolic investigations is low, ranging from 0.8 to 3 percent (table 5) [35,96]. Exome/genome sequencing techniques increasingly identify genetic abnormalities that cause IEM; thus, the incremental yield of routine metabolic testing when exome/genome sequencing is performed is quite low [18].
When performing metabolic testing, the initial tests include [21]:
●Measurement of plasma amino acids
●Urine organic acids
●Acylcarnitine profile
●Serum electrolytes, ammonia, and lactate levels
Additional testing should be guided by a metabolic specialist. Other possible tests include very long chain fatty acids, 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 [60,96,97]. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Developmental delay'.)
Fluorescence in situ hybridization — Chromosomal rearrangements in the gene-rich subtelomeric region are identified in approximately 1 to 5 percent of children with ID [98,99]. Molecular screening using FISH of subtelomeric probes was used widely in the past to identify these abnormalities; however, CMA has largely replaced FISH since the majority of diagnostic CMA arrays offer dense coverage of subtelomeric regions (table 5). FISH may be substituted for targeted analysis if CMA is not available. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Fluorescence in situ hybridization'.)
Additional evaluation
Blood lead level — Targeted lead screening should be performed if there are relevant exposures (table 6). (See "Childhood lead exposures: Exposure and prevention", section on 'Exposure' and "Screening tests in children and adolescents", section on 'Lead risk assessment'.)
Screening for lead exposure and poisoning in pregnant and lactating individuals is discussed separately. (See "Lead exposure, toxicity, and poisoning in adults: Clinical manifestations and diagnosis", section on 'Pregnancy'.)
Lead toxicity is an uncommon cause of ID in the United States. However, 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, elevated blood lead levels were more commonly detected in children with behavioral and/or developmental problems compared with controls (12 versus 0.7 percent) [100].
Lead is the most common environmental neurotoxin. Lead exposure can harm cognitive and neurodevelopmental functioning at any exposure level [101]. 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'.)
Iron studies and B12 level — Iron or vitamin B12 deficiency during pregnancy or early childhood can impact neurocognitive development leading to permanent impairment.
Children with risk factors (table 7) or clinical concern for iron deficiency or vitamin B12 deficiency should have iron studies and/or B12 levels obtained. The approach to testing is described elsewhere. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Laboratory testing' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Laboratory testing'.)
Screening for anemia and iron deficiency during pregnancy is discussed separately. (See "Anemia in pregnancy", section on 'Screening for anemia and iron deficiency'.)
Neuroimaging — Neuroimaging is not routinely necessary in the evaluation of children with ID, but may be warranted if any of the following are present [60,102]:
●Seizures
●Progressive or degenerative neurologic symptoms
●Abnormal head circumference (microcephaly or macrocephaly)
●Focal neurologic deficits
Magnetic resonance imaging (MRI) is the preferred modality in this setting. Consultation with a pediatric neurologist is appropriate in these cases.
Abnormal findings on neuroimaging may be seen in approximately 25 to 30 percent of children with moderate to severe GDD/ID; however, most abnormalities are nonspecific, and often do not lead to a specific diagnosis or alter clinical management [60,63,103,104]. 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 [104,105].
REFERRAL AND FOLLOW-UP —
Referral to a pediatric geneticist is valuable for many children with ID. Referral is generally warranted for children with syndromic features, abnormal results of genetic testing, or unexplained moderate to severe ID, particularly if exome or genome sequencing testing is being considered. The consultation may yield a definitive diagnosis and can facilitate genetic counseling for the family and appropriate management of the patient.
Depending on the cost and the available resources, clinical geneticists may recommend exome or genome sequencing after appropriate pretest counseling and informed consent [74]. In a child with suspected genetic disorder and a nondiagnostic exome or genome sequencing study, re-analysis is recommended after a 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
●Definition and prevalence – ID is characterized by deficits in intellectual and adaptive functioning that affect at least one (but typically all) of the three adaptive domains (conceptual, social, and/or practical (table 1)) with varying severity (table 2). In the general population, the prevalence of ID is approximately 1 to 2 percent. ID is mild in approximately 85 percent of affected individuals. (See 'Epidemiology' above and "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis".)
●Causes
•Genetic causes – 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 causes – Nongenetic causes of ID include (see 'Nongenetic causes' above):
-Congenital infections
-Teratogens such as alcohol, lead, and valproate
-Nutritional deficiencies (eg, early iron deficiency, vitamin B12 deficiency)
-Perinatal insults related to preterm birth, hypoxia, infection, trauma, and/or intracranial hemorrhage
-Acquired causes, including accidental or nonaccidental trauma, central nervous system (CNS) hemorrhage, CNS infection, CNS hypoxic insult (eg, near-drowning), brain tumors, congenital hypothyroidism, environmental toxins (eg, lead exposure), psychosocial deprivation, and malnutrition
●Approach to etiologic evaluation – Th selection and sequence of diagnostic tests to identify a cause in children with ID is individualized according to the clinical findings and availability of specific tests. The evaluation begins with a detailed history (including family history and review of newborn screening results) and physical examination (including neurologic examination and evaluation for dysmorphic features). (See 'Approach to etiologic evaluation' above.)
•Clinical suspicion for a specific disorder – In children with features suggestive of a specific diagnosis, the evaluation begins with targeted testing for the specific syndrome or disorder. Some common examples are summarized in the table (table 4). (See 'Clinical suspicion for a specific disorder' above.)
•Genetic testing for children with unexplained ID – For individuals with unexplained ID (ie, those without features suggestive of a specific diagnosis and those with negative results of specific tests), we offer genetic testing. Genetic testing can provide diagnostic and prognostic information, it allows for informative genetic counseling, and it may identify conditions that require further medical evaluation or treatment. (See 'Rationale for genetic testing' above.)
Referral to a clinical geneticist is generally warranted for children with syndromic features, abnormal results of genetic testing, or unexplained moderate to severe ID, particularly if exome or genome sequencing is being considered. (See 'Referral and follow-up' above.)
-First-line genetic tests – First-line genetic tests in children with unexplained ID include exome or genome sequencing or chromosomal microarray (CMA) (algorithm 1). The diagnostic yield is higher for exome/genome sequencing compared with CMA (table 5). (See 'Chromosomal microarray analysis' above and 'Exome or genome sequencing' above.)
-Second-line tests – Other tests that may be performed in the evaluation of unexplained ID include fragile X testing, G-banded karyotype, metabolic testing, and fluorescence in situ hybridization (FISH) (table 5). These tests can be used if exome/genome sequencing and CMA are not available or not chosen by the family/caregivers. In addition, selective use of these tests may be appropriate in specific clinical circumstances, as discussed above. (See 'Other genetic tests' above.)
•Selective use of other tests
-Blood lead level – Blood lead testing should be performed if there are risk factors for toxic lead exposure. (See "Childhood lead exposures: Exposure and prevention" and "Screening tests in children and adolescents", section on 'Lead risk assessment'.)
-Iron studies and B12 level – Children with risk factors (table 7) or clinical concern for iron deficiency or vitamin B12 deficiency should have iron studies and/or B12 levels obtained. The approach to testing is described elsewhere. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Laboratory testing' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Laboratory testing'.)
-Neuroimaging – 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 (MRI) is the preferred imaging modality. (See 'Neuroimaging' above.)
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