Autism Spectrum Disorder Genetics: Diverse Genes with Diverse Clinical Outcomes
Open accessAbstract
The last several years have seen unprecedented advances in deciphering the genetic etiology of autism spectrum disorders (ASDs). Heritability studies have repeatedly affirmed a contribution of genetic factors to the overall disease risk. Technical breakthroughs have enabled the search for these genetic factors via genome-wide surveys of a spectrum of potential sequence variations, from common single-nucleotide polymorphisms to essentially private chromosomal abnormalities. Studies of copy-number variation have identified significant roles for both recurrent and nonrecurrent large dosage imbalances, although they have rarely revealed the individual genes responsible. More recently, discoveries of rare point mutations and characterization of balanced chromosomal abnormalities have pinpointed individual ASD genes of relatively strong effect, including both loci with strong a priori biological relevance and those that would have otherwise been unsuspected as high-priority biological targets. Evidence has also emerged for association with many common variants, each adding a small individual contribution to ASD risk. These findings collectively provide compelling empirical data that the genetic basis of ASD is highly heterogeneous, with hundreds of genes capable of conferring varying degrees of risk, depending on their nature and the predisposing genetic alteration. Moreover, many genes that have been implicated in ASD also appear to be risk factors for related neurodevelopmental disorders, as well as for a spectrum of psychiatric phenotypes. While some ASD genes have evident functional significance, like synaptic proteins such as the SHANKs, neuroligins, and neurexins, as well as fragile x mental retardation-associated proteins, ASD genes have also been discovered that do not present a clear mechanism of specific neurodevelopmental dysfunction, such as regulators of chromatin modification and global gene expression. In its sum, the progress from genetic studies to date has been remarkable and increasingly rapid, but the interactive impact of strong-effect genetic lesions coupled with weak-effect common polymorphisms has not yet led to a unified understanding of ASD pathogenesis or explained its highly variable clinical expression. With an increasingly firm genetic foundation, the coming years will hopefully see equally rapid advances in elucidating the functional consequences of ASD genes and their interactions with environmental/experiential factors, supporting the development of rational interventions.
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Studies on hcASD genes and iPSC-derived ASD neurons highlight signaling pathways that are commonly disrupted, such as PI3K/AKT, RAS/ERK, WNT and β-catenin.
“Consistently, studies on hcASD genes and iPSC-derived ASD neurons highlight signaling pathways that are commonly disrupted, such as PI3K/AKT [79, 80], RAS/ERK [79, 80, 82, 83], WNT and β-catenin [57, 83, 84].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [83]
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The ASD Living Biology: from cell proliferation to clinical phenotype
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- Authors
- Talkowski, M. E., Minikel, E. V., & Gusella, J. F.
- Affiliations
- Harvard University (US)
- Corresponding author
- Gusella, James F.
- Venue
- Harvard Review of Psychiatry
- Published
- 2014-03
- Volume
- 22
- Issue
- 2
- Pages
- 65-75
- ISSN
- 1067-3229 (ISSN-L)
- PMC
- PMC9369102
- OpenAlex
- W2018775541
- Cited by
- 72
- References
- 115
- Citations by year
- 2026: 2 · 2025: 4 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 6 · 2019: 3 · 2018: 11 · 2017: 7 · 2016: 15 · 2015: 10 · 2014: 4
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Harvard Review of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH095867, R00MH095867, K99MH095867)
- National Institute of General Medical Sciences (GM061354, P01GM061354)
- 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 etiology, copy number variation, single nucleotide polymorphisms, heritability, chromosomal abnormalities, neurodevelopmental disorders, psychiatric phenotypes, synaptic proteins, FMRP, chromatin modification, gene-environment interaction, ASD pathogenesis
- MeSH terms
- Child Development Disorders, Pervasive, Humans, Gene-Environment Interaction
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