Genetics and genomics of autism spectrum disorder: embracing complexity
Open accessAbstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by impairments in social communication and social interaction and the presence of repetitive behaviors and/or restricted interests. ASD has profound etiological and clinical heterogeneity, which has impeded the identification of risk factors and pathophysiological processes underlying the disorder. A constellation of (i) types of genetic variation, (ii) modes of inheritance and (iii) specific genomic loci and genes have all recently been implicated in ASD risk, and these findings are currently being extended with functional analyses in model organisms and genotype-phenotype correlation studies. The overlap of risk loci between ASD and other NDDs raises intriguing questions around the mechanisms of risk. In this review, we will touch upon these aspects of ASD and how they might be addressed.
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- Premisecitation
More than half of the risk of developing ASD is attributable to genetic variation.
“Studies making use of twin pairs (7)(8)(9)(10)(11), families (12) and populations (11,13) have provided estimates that over half of risk of developing ASD resides with genetic variation”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
The most prominent phenotype of ADNP knockdown in zebrafish is defective erythropoiesis.
“the most prominent phenotype of ADNP knockdown in zebrafish is defective erythropoiesis (63).”
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- Premisecitation
Polygenic risk from many SNPs is a major determinant of ASD variance.
“However, polygenic risk due to a large number of SNPs is a major determinant of the variance for ASD (11,12,16) (Fig. 1).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
About 57% of individuals with a de novo loss-of-function SNV and an ASD diagnosis would not be affected if they did not have the SNV.
“and 57% of the individuals with a de novo loss-of-function SNV and an ASD diagnosis would not be affected if they did not have the SNV”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] source
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- Premisecitation
Common SNP variation contributes to ASD risk in carriers of either a de novo CNV or a de novo loss-of-function SNV.
“but common variation, in the form of SNPs, contributes in either case.”
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- Premisecitation
Whole-exome sequencing of large ASD cohorts has expanded the set of known ASD-linked genes beyond those found by traditional genetic approaches and targeted sequencing.
“Recent whole-exome sequencing analyses of large ASD cohorts (21)(22)(23)(24)(25)(26)(27)(28)(29) have expanded the repertoire of known genes harboring ASD-linked mutations that were previously identifiable only by traditional genetic approaches and targeted sequencing (14,15).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
A single common SNP has a very weak effect on ASD risk.
“Common variation in the form of single-nucleotide polymorphisms (SNPs) has a very weak effect when a given SNP is considered individually (16).”
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- Premisereasoning
ASD genomewide association studies have not identified reproducible SNP associations.
“and have failed to identify reproducible SNP associations (16)(17)(18)(19)(20).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Gaugler et al. estimated the probability that carriers of de novo CNVs or SNVs would be affected if they had not carried those mutations, using a well-defined ASD cohort.
“Gaugler et al. (11) provide a clear example by estimating the probability for carriers of de novo mutations (CNV or SNV) to be affected if they were not carriers of these mutations, using a well defined ASD cohort (11).”
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- Premisecitation
About 80% of individuals with a de novo CNV and an ASD diagnosis would not be affected if they did not have the CNV.
“They found that ∼80% of the individuals with a de novo CNV and an ASD diagnosis would not be affected if they did not have the CNV”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] source
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- Premisecitation
Genetic variation accounts for the elevated recurrence risk of ASD and related phenotypes in families.
“which explains the elevated recurrence risk of ASD and associated phenotypes observed in families (13).”
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- Premisecitation
Rare genetic risk variants identified so far have a very large effect on individual ASD risk.
“Rare genetic risk variation identified to date, in contrast, has a very substantial effect on individual risk.Recent whole-exome sequencing analyses of large ASD cohorts (21)(22)(23)(24)(25)(26)(27)(28)(29) have expanded the repertoire of known genes harboring ASD-linked mutations”
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Adnp heterozygous mice show sex-related impairment in learning and memory behaviors.
“Adnp +/-mice display a sex-related impairment in learning and memory behaviors (66)”
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- Premisecitation
One mechanism mediating the paternal age effect on ASD risk is the higher rate of de novo single-nucleotide variants and copy number variants with advancing paternal age.
“In the case of paternal age, one mediating mechanism lies in the increased rate of de novo SNV and CNV with advancing paternal age (22,24,25,43,44).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Simulations based on the observed number of recurrently disrupted genes estimate that there are about 600 to 1200 ASD risk genes.
“Simulations based on the observed number of recurrently disrupted genes have estimated that there are some 600-1200 ASD risk genes (21,24,26,51).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationnone given
Genetic manipulation of ASD risk genes in model organisms and subsequent functional analyses are beginning to reveal their biology and complex phenotypic associations.
“Genetic manipulations of these genes in model organisms and subsequent functional analyses are beginning to provide insights into their biology and are highlighting complex phenotypic associations with these genes.”
Quote in the paperNot a substantial claim- Rests on an assumption: Phenotypes and functional findings from model organisms for ASD risk genes are informative about human ASD pathobiology.
- Premisecitation
In the Simons Simplex Collection, individuals with ASD and IQ below 100 have an excess of de novo loss-of-function mutations compared with higher functioning individuals.
“In the SSC, individuals with ASD and IQ < 100 have an excess of de novo loss-of-function mutations in comparison to their higher functioning counterparts (97,98)”
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Deep phenotyping of 15 patients with CHD8 mutations led to identification of a proposed ASD subtype.
“Deep phenotyping of 15 patients with CHD8 mutations has led to the identification of a proposed ASD subtype (56)”
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- Premisecitation
Genotype-first studies with comprehensive clinical characterization of cohorts sharing an etiology show high variability in expressivity of recurrent CNVs and single-gene mutations.
“Using a genotype-first approach, studies reporting the comprehensive clinical characterization of cohorts of patients with shared etiology have shown a high degree of variability in the expressivity of recurrent CNVs and mutations in single genes (95).”
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- Premisecitation
Chromosomal microarray and sequencing studies have found substantial genetic overlap between ASD and other neurodevelopmental and neurological conditions, including intellectual disability, epilepsy, and schizophrenia.
“Chromosomal microarray and sequencing studies have found remarkable genetic overlap between ASD and other neurodevelopmental and neurological conditions, including ID, epilepsy and schizophrenia (92,93).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
CHD2 mutations have been detected in individuals diagnosed with ASD, intellectual disability, or epilepsy.
“Mutations in CHD2 have been detected in individuals with a diagnosis of ASD (22), ID (73) or epilepsy (82,83,87,89)”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationcitation
ASD and cardiac arrhythmia might be common manifestations of a distinct nosological entity.
“As most ANK2 missense mutations in patients with cardiac arrhythmia map to both cardiac and neuronal isoforms (88), ASD and cardiac arrhythmia might be common manifestations of a distinct nosological entity.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [88] source
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- Premisecitation
Deep phenotyping of 10 patients with ADNP mutations led to identification of a potential new syndrome.
“Deep phenotyping of 10 patients with ADNP mutations has led to the identification of a potential new syndrome (67).”
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- Premisecitation
The same study showed the value of using quantitative rather than dichotomous measures to assess and account for familial influence.
“and shown the value of using quantitative rather than dichotomous measures to better assess and account for such familial influence (50).”
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- Premisecitation
22q11.2 and 16p11.2 deletions are associated with variable severity with various neuropsychiatric disorders, including ASD, intellectual disability, and schizophrenia.
“Both deletions are in fact associated, with variable severity, with various neuropsychiatric disorders, including ASD, ID and schizophrenia, among others (50,96).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Incomplete penetrance is true for most of the ASD genes and loci identified so far.
“which is true for most of the genes and loci that have been identified.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
A study of 22q11.2 deletion carriers identified a common CNV that could act as a modifier of the cardiac phenotype.
“A study focussing on the variable expressivity of CHD in carriers of 22q11.2deletion has identified a common CNV that could act as a modifier on the cardiac phenotype in individuals with the syndrome (49).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [49] source
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- Interpretationreasoning
Aggregating data from multiple neurodevelopmental disorders is an efficient way to increase power for gene discovery.
“while also making it clear that aggregating data from multiple NDDs are an efficient means to enhance power for gene discovery.”
Quote in the paperNot a substantial claim - Premisecitation
Recent discoveries indicate shared genes and pathways between ASD and congenital heart disease.
“In fact, recent discoveries indicate shared genes and pathways between ASD and congenital heart disease (CHD) (26,93,94).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
A study of 56 individuals with de novo 16p11.2 deletions showed the importance of family background for clinical variability.
“a study on 56 individuals with de novo 16p11.2deletions has shown the importance of family background (which in turn might be mediated by common variation and/or non-genetic factors) on clinical variability”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] source
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- Classified as probably not a substantial claim. 7
- May combine two claims. 24
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PremisecitationOther neurodevelopmental, neurological, and medical conditions are common but highly variable in ASD.
“Other NDDs [e.g.attention deficit hyperactivity disorder (ADHD) and schizophrenia], neurological disorders (e.g.motor deficits, sleep disturbances and epilepsy) and medical conditions (e.g.gastrointestinal problems, congenital anomalies and allergy) are also common in ASD although highly variable (6).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Aldinger, 2015, Patterns of risk for multiple co-occurring medical conditions replicate across distinct cohorts of children with autism spectrum disorder, Autism Res. source
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PremisecitationASD shows wide phenotypic variability and follows heterogeneous developmental trajectories.
“ASD manifests with broad phenotypic variability and evolves along heterogeneous developmental trajectories (1).”
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PremisecitationAbout 30% of people with ASD remain minimally verbal throughout life.
“For example, ∼30% of individuals with ASD remain minimally verbal throughout life (5)”
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PremisecitationASD symptom severity varies and is inversely related to adaptive functioning.
“Severity of ASD symptoms is variable and inversely correlates with adaptive functioning (2).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] source
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PremisecitationAbout 60% of people with ASD have co-occurring intellectual disability.
“and ∼60% have co-occurring intellectual disability (ID) (3).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Vivanti, 2013, Intellectual development in autism spectrum disorders: new insights from longitudinal studies, Front. Hum. Neurosci. source
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PremisecitationLanguage ability and cognitive function vary widely in ASD and predict later outcome.
“Language abilities and cognitive function, two domains strongly affecting adaptive behavior (2,3) and predicting later outcome (4), also have a broad range in ASD.”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationMore than 50 high-risk ASD genes have emerged from large-scale sequencing studies, most under an autosomal dominant model.
“To date, in addition to causal and highly penetrant genes and genomic loci identified before whole-exome sequencing (15,30), over 50 high-risk genes have emerged from the large-scale sequencing studies (21)(22)(23)(24)(25)(26), most under a model of autosomal dominant variation.”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationTransmitted protein-disrupting variants can strongly influence ASD risk when inherited dominantly, with odds ratios around 3, or when biallelic disruption acts recessively or X-linked, with odds ratios above 2.
“Transmitted variants that disrupt protein function can also have a strong influence on risk when inherited and acting dominantly (odds ratios ∼3) (26) or if resulting in biallelic disruption and acting in a recessive (34,35) or X-linked (34) manner (odds ratio above 2).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationANK2 has been consistently associated with ASD and also with cardiac arrhythmia.
“ANK2 has been consistently associated with ASD (22,26,80) and also with cardiac arrhythmia (OMIM no.600919) (78).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationASD genomewide association studies to date have been underpowered because individual SNPs have weak effects and sample sizes have been insufficient.
“As a result, genomewide association studies carried out to date have been underpowered due to the weak effect of individual SNPs (16) and, hence, insufficient sample size [the largest study has analyzed 2,705 families (16)]”
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PremisecitationMouse models with ANK2 disruption show neurological and cardiac phenotypes.
“Consistently, neurological (76) and cardiac (77,78) phenotypes have been described in mouse models with a disruption of this gene.”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationADNP is essential for brain development.
“although ADNP is essential for brain development (64)”
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InterpretationreasoningThe liability threshold model helps explain the relatively high sibling risk, the greater mutational burden in ASD probands than unaffected siblings, etiological heterogeneity within affected sibling pairs, and variable expressivity of certain loci.
“The model helps in the understanding of the relatively high risk for siblings of individuals diagnosed with ASD (13,46), the increased mutational burden in ASD probands compared with their unaffected siblings (22,28), etiological heterogeneity even within pairs of affected siblings (47,48) and, as we shall discuss further, the variable expressivity of certain loci (49,50) (Fig. 1).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationPaternal age and maternal age are each independently associated with ASD risk.
“Paternal (38)(39)(40)(41) and maternal (41,42) age have been independently associated with ASD risk.”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationRare ASD risk variants can be inherited from unaffected parents or can arise de novo during meiosis.
“Rare variants can be inherited from unaffected parents (26,28,34,35) or arise as de novo mutations during the meiotic divisions of gametogenesis (21)(22)(23)(24)(25)(26)(27)(30)(31)(32)36,37).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAdvancing maternal age is a known risk factor for chromosomal aberrations.
“but advancing maternal age is a known risk factor for chromosomal aberrations (45).”
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PremisecitationAutosomal de novo loss-of-function single-nucleotide variants act dominantly and carry a large individual risk, with odds ratios of 20 or more for genes identified so far.
“Autosomal de novo loss-of-function SNV has been identified that acts in a dominant manner and carries a large burden for individual risk, with odds ratios of 20 or above for genes identified to date (24,26).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationRare chromosomal rearrangements, copy number variants, single-nucleotide variants, and indels all contribute to ASD risk.
“At this point, it is clear that rare microscopically detectable chromosomal rearrangements (14,15), submicroscopic deletions or duplications (CNV or smaller structural variation) (27,(29)(30)(31)(32), single-nucleotide variation (SNV) and small deletions and duplications (indels) (21)(22)(23)(24)(25)(26)(33)(34)(35) all contribute to risk.”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationNon-genetic sources of ASD risk exist, but the mechanisms behind these associations remain unclear.
“Beyond genetic factors, there is evidence for a role of non-genetic sources of risk in ASD, although the mechanisms underlying these associations are still unclear.”
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InterpretationcitationThe findings support a model in which inherited common and rare variation create a susceptibility substrate, and additional high-risk genetic and/or non-genetic factors push liability past a threshold to cause ASD.
“These findings are consistent with a model whereby inherited variation, both common (11) and rare (26,28), defines a substrate of susceptibility, and additional high-risk genetic (including de novo, recessive and X-linked variation) and/or non-genetic factors then act on this substrate to surpass the liability threshold that results in ASD (Fig. 1).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningIn many studies of this kind, ascertainment from samples selected for phenotypes of interest likely introduces bias.
“although for this and many such studies the ascertainment was primarily from samples ascertained on the basis of phenotypes of interest, likely introducing biases.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationCHD2 has been associated with ASD, intellectual disability, epilepsy, and photosensitivity.
“CHD2 has been associated with ASD (22,23), ID (73), epilepsy (82,87) and photosensitivity (83).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
InterpretationreasoningIntegrating genetic discoveries and clinical observations in ASD suggests that common and rare variations combine to produce a diagnosis, and possibly that common variation defines the specific phenotypes manifested.
“The integration of genetic discoveries and clinical observations in ASD is delineating a scenario whereby common and rare variations combine to produce a diagnosis, and, possibly, common variation (genetic or familial background) defines the specific phenotypes that are manifested.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation22q11.2 and 16p11.2 deletions can also be found in healthy individuals, which is consistent with incomplete penetrance.
“The deletions can also be detected in healthy individuals, an observation consistent with incomplete penetrance (50,96)”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationGrouping by ASD diagnostic category, IQ, ASD severity, insistence on sameness, and symptom profiles did not significantly increase genetic homogeneity as defined by SNPs and did not yield more discoveries for common variation.
“However, in one recent study, grouping by ASD diagnostic category, IQ, ASD severity, insistence on sameness and symptom profiles did not significantly increase genetic homogeneity, at least as defined by SNPs nor does it yield more discoveries for common variation (104,105).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIn the Simons Simplex Collection, individuals with ASD but not intellectual disability have a higher rate of family history of psychiatric disease and thus a greater familial burden.
“whereas individuals with ASD but not ID have a higher rate of family history of psychiatric disease and thus a greater familial burden (98).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [98] source
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InterpretationreasoningThese observations may challenge the validity of ASD as a specific construct and support shared risk across diverse neurodevelopmental disorders.
“All of these observations may complicate the validity of ASD as a specific construct and support a shared risk between diverse NDDs.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningASD risk loci and genes identified so far rarely map exclusively to ASD, which raises questions about pleiotropy and makes genotype-phenotype correlations complex.
“The scenario emerging from these few examples shows how ASD risk loci and genes identified to date rarely map exclusively to ASD (Figs 1 and 2), raising questions about pleiotropy or other mechanisms of action and rendering genotype-phenotype correlations complex.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationTBR1 has been implicated in ASD and intellectual disability.
“TBR1 has been implicated in ASD (21,22,25,26) and ID (73).”
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InterpretationcitationCommon variation may determine which specific traits are expressed when a highly penetrant mutation occurs, and findings in 22q11.2 and 16p11.2 deletion syndromes provide some support for this.
“One intriguing hypothesis is that common variation may be a factor determining the expression of specific traits when a highly penetrant mutation occurs (Fig. 1), and recent findings in both 22q11.2 and 16p11.2deletion syndromes provide some support of this.”
Quote in the paperSubstantial claim0 of 2 sources checked
The paper relies on this without support.
Phenotypes and functional findings from model organisms for ASD risk genes are informative about human ASD pathobiology.
“Genetic manipulations of these genes in model organisms and subsequent functional analyses are beginning to provide insights into their biology”
Claims other papers make about this one
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In individuals carrying de novo CNVs or gene mutations, psychiatric diagnoses vary and only a subset meet criteria for ASD.
“In subjects who carry de novo CNVs or gene mutations, psychiatric diagnoses are variable and typically only a subset meet criteria for ASD (De Rubeis and Buxbaum, 2015; Malhotra and Sebat, 2012).”
From Getting to the cores of autism (2019) · cites this paper as De Rubeis and Buxbaum, 2015
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BackgroundStructural Variation of Chromosomes in Autism Spectrum Disorder
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- Authors
- De Rubeis, S., & Buxbaum, J. D.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Buxbaum, Joseph D.
- ORCID
- Buxbaum, Joseph D.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-07-17
- Volume
- 24
- Issue
- R1
- Pages
- R24-R31
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4675826
- OpenAlex
- W1759848617
- Semantic Scholar
- 14a410487cc74019a99fcf27a5d0f070f2c0acad
- Cited by
- 208
- References
- 32
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 17 · 2023: 15 · 2022: 12 · 2021: 26 · 2020: 32 · 2019: 22 · 2018: 17 · 2017: 20 · 2016: 25 · 2015: 4
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (U01MH100233)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- autism spectrum disorder, genetic risk factors, genetic loci, mode of inheritance, genetic variation, neurodevelopmental disorders, genotype-phenotype correlation, model organisms, etiologic heterogeneity
- MeSH terms
- Autism Spectrum Disorder, Animals, Humans, Risk Factors, Genetic Variation, Genomics, Inheritance Patterns, Genetic Association Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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