Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders
Open accessAbstract
Autism spectrum disorders (ASDs) are a heterogeneous group of neuro-developmental disorders. While significant progress has been made in the identification of genes and copy number variants associated with syndromic autism, little is known to date about the etiology of idiopathic non-syndromic autism. Sanger sequencing of 21 known autism susceptibility genes in 339 individuals with high-functioning, idiopathic ASD revealed de novo mutations in at least one of these genes in 6 of 339 probands (1.8%). Additionally, multiple events of oligogenic heterozygosity were seen, affecting 23 of 339 probands (6.8%). Screening of a control population for novel coding variants in CACNA1C, CDKL5, HOXA1, SHANK3, TSC1, TSC2 and UBE3A by the same sequencing technology revealed that controls were carriers of oligogenic heterozygous events at significantly (P < 0.01) lower rate, suggesting oligogenic heterozygosity as a new potential mechanism in the pathogenesis of ASDs.
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In humans, mutations in MAPK3 and TAOK2 but not in KCTD13 have been found in ASD cases.
“In humans, mutations in MAPK3 [92] and TAOK2 [93, 94] but not in KCTD13 [85, 95] have been found in ASD cases.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [92]
Missense variants in MAPK3 are identified in ASD probands, but no loss of function MAPK3 mutations have been reported in ASD, leaving the direct link to ASD uncertain.
“Missense variants in MAPK3 are identified in ASD probands [85, 92], but no loss of function (LoF) MAPK3 mutations have been reported in ASD, leaving the direct link to ASD uncertain.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [92]
Many missense mutations have been identified in SHANK3, but their clinical relevance has not been determined.
“Many missense mutations have been identified in SHANK3 (Gauthier et al., 2009; Moessner et al., 2007; Schaaf et al., 2011), but their clinical relevance has not been determined.”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Schaaf et al., 2011
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- Authors
- Schaaf, C. P., Sabo, A., Sakai, Y., Crosby, J., Muzny, D., Hawes, A., Lewis, L., Akbar, H., Varghese, R., Boerwinkle, E., Gibbs, R. A., & Zoghbi, H. Y.
- Affiliations
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- The University of Texas Health Science Center at Houston (US)
- Corresponding author
- Gibbs, R. A.
- Zoghbi, H. Y.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-05-30
- Volume
- 20
- Issue
- 17
- Pages
- 3366-3375
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3153303
- OpenAlex
- W2102467876
- Cited by
- 175
- References
- 45
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 11 · 2020: 12 · 2019: 12 · 2018: 11 · 2017: 9 · 2016: 12 · 2015: 10 · 2014: 20 · 2013: 24 · 2012: 21
- FWCI
- 11.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Human Molecular Genetics (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Simons Foundation
- Simons Foundation Autism Research Initiative
- Japan Society for the Promotion of Science (23810025)
- National Human Genome Research Institute (U54HG003273)
- National Institute of Neurological Disorders and Stroke (R01NS057819)
- 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, high-functioning autism, de novo mutations, autism susceptibility genes, copy number variation, CACNA1C, CDKL5, HOXA1, SHANK3, TSC1, TSC2, UBE3A, genetic pathogenesis
- MeSH terms
- Adolescent, Child, Child Development Disorders, Pervasive, Child, Preschool, Heterozygote, Humans, Male, Mutation, Genetic Predisposition to Disease
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