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. 2011 Sep 1;20(17):3366-75.
doi: 10.1093/hmg/ddr243. Epub 2011 May 30.

Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders

Christian P Schaaf  1 , Aniko Sabo, Yasunari Sakai, Jacy Crosby, Donna Muzny, Alicia Hawes, Lora Lewis, Humeira Akbar, Robin Varghese, Eric Boerwinkle, Richard A Gibbs, Huda Y Zoghbi
Affiliations

Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders

Christian P Schaaf et al. Hum Mol Genet. .

Abstract

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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Figures

Figure 1.
Figure 1.
De novo mutations and evolutionary conservation. Six de novo mutations detected by Sanger sequencing of 21 autism susceptibility genes in 339 probands from the Simons Simplex Collection. Reference amino acids are displayed in black, variant amino acids in the patients in red color. Amino acids from different species which differ from the human sequence are displayed in green. Single line, no amino acids in the aligned species. Double line, aligned species has no alignable amino acids in the respective region. Information based on UCSC Genome Browser human genome build 18.
Figure 2.
Figure 2.
Proposed models of inheritance for ASDs. Left panel: syndromic autism is mostly caused by severe loss-of-function mutations of specific genes, with each gene causing a specific syndrome. Right panel: non-syndromic autism may be caused by milder mutations in genes that are known to cause syndromic autism or by mutations in novel genes, unrelated to syndromic autism. Oligogenic heterozygosity of hypomorphic variants in genes known to cause syndromic autism may have a cumulative effect, resulting in non-syndromic autism. Mutations may be point mutations or coding indels, as well as CNVs.
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