Autism Spectrum Disorder (ASD) is a neurodevelopmental psychiatric condition that shares significant clinical and genetic overlap with intellectualdisability (ID) and other neurodevelopmental disorders. Genetic testingin ASD lags far behind that for ID, even though Professional Societiesrecommend genetic testing for all ASD individuals and insurance reimbursement is relatively good. The core competencies for child and adolescent psychiatrists include determining the etiology and diagnosisfor all childhood psychopathology, including ID and ASD. Child psychiatrists should recommend and order genetic testing by exomeor genome sequencing on all children with ASD.
Key points
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Autism spectrum disorder (ASD) is one of the most genetically influenced of all human disorders, with significant clinical utility for appropriate genetic testing.
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A causal genomic variant can be identified in ∼20% of ASD patients, and diagnostic genetic testing is recommended by relevant professional societies for all individuals with ASD.
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Exome or genome sequencing with copy number analysis is recommended as the first-line genetic test for all patients with ASD and other neurodevelopmental disorders.
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Clinical genetic testing is widely available, with costs covered by most insurers, yet implementation in psychiatry lags far behind that of other medical specialties.
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Child and adolescent psychiatrists should recommend and order diagnostic genetic testing for all patients with ASD rather than referring to medical genetics clinics for evaluation and testing.
| AACAP | American Academy of Child and Adolescent Psychiatry |
| AAP | American Academy of Pediatrics |
| ASD | autism spectrum disorder |
| CAPs | child and adolescent psychiatrists |
| CHD8 | chromodomain helicase DNA binding protein 8 |
| CMA | chromosomal microarray |
| CNVs | copy number variants |
| DSM5 | Diagnostic and statistical manual of mental disorders, 5 th edition |
| GDD | global developmental delay |
| GWAS | genome wide association studies |
| ID | intellectual disability |
| IDD | intellectual and developmental disabilities |
| MODY5 | maturity-onset diabetes of the young type 5 |
| NDD | neurodevelopmental disorders |
| PGS | polygenic scores |
| SHANK3 | SH3 and multiple ankyrin repeat domains 3 |
Introduction
Autism spectrum disorder (ASD) is a neurodevelopmental psychiatric condition, which has extensive clinical overlap, as well as largely identical genetic etiology, with intellectual disability (ID) and other neurodevelopmental disorders (NDD). In the case of ID, it has been recognized for many years that there are many different genetic etiologies, from chromosomal aneuploidies (eg, Down syndrome due to trisomy 21), small chromosomal deletions or duplications (now referred to as copy number variants [CNVs]), to hundreds of single-gene disorders. , Given the extreme clinical variability in severity and other features of ID, it is not surprising that estimates of hundreds of different genes, when altered, can cause ID. Since it is estimated that 50% to 80% of the 20,000 human genes are expressed in the brain (ie, brain genes ), it follows that subtle disruptions of gene expression in any of these ∼10,000 brain genes could have a deleterious effect on cognitive function.
In contrast, early expectations were that ASD might have a more limited set of specific genetic etiologies. However, all clinicians who see patients with ASD are aware of the extreme heterogeneity in clinical presentation, leading to the common statement “If you’ve seen one person with ASD, you’ve seen one person.” Given this extreme clinical heterogeneity, it should not be surprising that the etiology of ASD is equally heterogeneous to that of ID, and that subtle perturbation of many of our 10,000 brain genes could have deleterious impacts on social behavior and communication.
Clinical diagnosis of autism spectrum disorder and other neurodevelopmental disorders
The Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition, Text Revision (DSM-5-TR) describes the broad category of NDD, which includes ASD, ID, global developmental delay (GDD), communication disorders, attention deficit/hyperactivity disorder, specific learning disorders, and motor disorders. Broader definitions of NDD include epilepsy and cerebral palsy. , Taken together, NDD have a prevalence of 17% in US children aged 3 to 17 years and, as a group, are among the most prevalent chronic medical conditions in pediatrics.
NDD are characterized by deficits in cognitive ability, social behavior, language, and/or motor skills resulting in impairment of adaptive functioning in personal, social, school, and occupational functioning. , The clinical diagnostic categories for NDD are based on the presence of descriptive, phenomenological symptom clusters. Specifically, ASD is defined by impairments in social communication, repetitive behaviors, and restricted interests, the presence and severity of which vary widely among individuals, as alluded to above. ID, which is a common ASD co-occurring condition, is characterized by significant limitations in both intellectual functioning and adaptive behavior. Although full-scale intelligence quotient (IQ) score is not a requirement for the clinical diagnosis of ID, historically an IQ of 70 or below has been used as a major part of arriving at this diagnosis. For a more detailed discussion of clinical criteria and standardized assessments for ASD and related NDD, see Myers and Challman.
Genetic etiologies of autism spectrum disorder and other neurodevelopmental disorders
Twin and family studies have shown ASD and other NDD to be highly genetic, with heritability estimates for ASD ranging from 64% to 97%. , A great deal has been learned over the last 15 years about the genetic architecture of ASD and NDD, including the role of common and rare genetic variation. As indicated in Table 1 , the core competencies of child and adolescent psychiatrists (CAPs) include the evaluation, clinical diagnosis, and treatment of NDD including both ASD and ID. In addition to the clinical diagnosis, CAPs are expected to understand the etiology of NDD, including genetic etiologies as determined by appropriate diagnostic genetic testing. Despite guidelines by the American Academy of Child and Adolescent Psychiatry (AACAP), the American Academy of Pediatrics (AAP), the American College of Medical Genetics and Genomics, and other professional groups recommending diagnostic genetic testing for individuals with ASD and/or ID ( Table 2 ), implementation in psychiatry lags far behind that of many other medical specialties. In this article, we will address current knowledge of the contribution of common and rare genetic variation to the etiology of ASD, as well as the clinical value of diagnostic genetic testing. We will not cover the role of pharmacogenomics testing in this article, as this is distinct from the types of diagnostic testing used in the medical evaluation of children with NDD, as described below.
| Organization | Core Competencies and Practice Parameters for Child and Adolescent Psychiatrists |
|---|---|
| ACGME a , |
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| ABPN b , |
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| AACAP c , |
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a Accreditation Council for Graduate Medical Education Requirements for Child and Adolescent Psychiatry, July 1, 2024.
b American Board of Psychiatry and Neurology Child and Adolescent Psychiatry Core Competencies Outline.
c American Academy of Child and Adolescent Psychiatry Practice Parameter for the Assessment and Treatment of Psychiatric Disorders in Children and Adolescents with Intellectual Disability (Intellectual Developmental Disorder), April, 2020.
| Organization | Recommendation(s) for Genetic Testing |
|---|---|
| AACAP a (2020) |
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| AAP b (2014, 2020) , |
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| Multidisciplinary Expert Consensus Panel (2019) |
|
| ACMG c , |
|
a American Academy of Child and Adolescent Psychiatry.
b American Academy of Pediatrics.
Common Genomic variation in Autism Spectrum Disorder and Other Neurodevelopmental Psychiatric Conditions: Significant Research Progress, but no Clinical Applications so far
For many common, complex human traits and medical conditions, variations with very small effect sizes are found in many genes (10s–100s) throughout the genome and contribute in a cumulative fashion to the chances of developing the trait or medical condition. Examples of polygenic traits include height, weight, and educational attainment. Genome wide association studies (GWAS) are modern research techniques, which can identify such small-effect variants anywhere in the genome, usually in noncoding deoxyribonucleic acid (DNA) regions thought to be near genes or other functional elements. , GWAS require very large case and control cohort sizes (in the thousands or tens of thousands) to power statistical analyses that can determine which individual loci reach genome-wide significance. For ASD, the largest GWAS meta-analysis included over 18,000 ASD cases and almost 28,000 controls and identified 5 genomic loci that met genome-wide significance.
GWAS methods aim to identify candidate genes or functional regions of the genome that contribute to disorder risk but do not take advantage of the hundreds or thousands of common variants that may have smaller effect sizes and do not reach genome-wide significance with current cohort sizes. Newer methods, referred to as polygenic scores (PGS), use all common variants in the genome that contribute to a phenotype or disorder risk. At present, PGS for various neurodevelopmental and psychiatric disorders are not sufficiently predictive to have any current clinical application (eg, they explain only 7% of the variance for schizophrenia) but may become clinically useful in the future. , As discussed below, common genetic variation as measured by PGS may help to predict which individuals with a rare variant are most likely to have significant clinical manifestations/diagnoses due to a susceptible rather than resilient genetic background. ,
This decades-long focus on GWAS as a research tool to identify common variants contributing to the probability of developing psychiatric conditions has overshadowed and been conflated with the growing list of rare genomic variants that have such large effect size, they can be considered causative of psychiatric conditions. It is important for psychiatrists to understand the distinction between research progress by GWAS in understanding common genetic contributions to risk of psychiatric conditions, and diagnostic genetic testing to identify the cause of psychiatric conditions, including ASD.
Rare Genomic Variants as Primary Cause of Autism Spectrum Disorder can be Identified in ∼20% of Cases by Clinically Available Diagnostic Genetic Testing
Chromosomal microarray (CMA) testing has been the standard first-tier genetic test for all individuals with ASD and/or ID since 2010, when the American College of Medical Genetics and Genomics (ACMG) endorsed an expert consensus statement recommending that CMA replace G-banded karyotype as the first-tier test. Fragile X testing was also recommended by the AAP (2014) and ACMG (2013), in conjunction with CMA, for all patients with ASD and/or ID. , Nearly a decade after the CMA consensus statement, an expert consensus statement published in 2019 by Srivastava and colleagues recommended that exome sequencing with copy number analysis replace CMA as the first-tier test for all NDD, including ASD and ID, in light of its higher yield and ability to detect sequence and copy number changes. This recommendation was reiterated for ID in an updated ACMG recommendation in 2021. Clinical genome sequencing has recently begun to replace exome sequencing as the diagnostic test of choice for ID and ASD in some centers, and professional recommendations will continue to evolve to keep pace with rapid advances in DNA technology.
Rare Pathogenic Variants in Hundreds of Genes can Cause Autism Spectrum Disorder and/or Intellectual Disability
It has been known for many years that certain recognizable single-gene disorders strongly increase the risk for ASD and/or ID (eg, fragile X syndrome, phosphatase and tensin homolog [ PTEN ] hamartoma tumor syndrome). , However, with the advances in exome and genome sequencing, the number of high confidence ASD genes has now increased to well over 100, with predictions that there may be 1,000 or more. Among the most common of these are CHD8 (chromodomain helicase DNA binding protein 8) and SHANK3 (SH3 and multiple ankyrin repeat domains 3). Loss of function mutations in these 2 genes causes ASD in ∼60%-70% of cases and ID in ∼75%-98% of cases. , Overall, genetic variants that increase liability for ASD also increase the chances of developing other mental health or medical conditions, a reflection of the phenotypic variability that characterizes psychiatric genetics. As discussed in detail elsewhere, there is not yet an example of a single gene that, when mutated, causes ASD but does not also cause ID in a high percentage of cases ( Table 3 ).
| Genomic Variant | ASD | GDD/ID | SSD | Any Neuropsychiatric Phenotype | Common Actionable Medical Features |
|---|---|---|---|---|---|
| PTEN , , | 25% | 35% | NA | 40% |
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| CHD8 , | 70% | 75% | 3% | ∼100% |
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| SHANK3 | 60% | 98% | 5% | ∼100% |
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| 22q11.2 deletion , , , | 20% | 45% | 25% | ∼100% |
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| 16p11.2 deletion , , | 20% | 30% | 3% | 90% |
|
| 17q12 deletion , , | 15% | 35% | 3% | 45% |
|
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