title: The Contribution of Mosaic Variants to Autism Spectrum Disorder.
abstract: De novo mutation is highly implicated in autism spectrum disorder (ASD). However, the contribution of post-zygotic mutation to ASD is poorly characterized. We performed both exome sequencing of paired samples and analysis of de novo variants from whole-exome sequencing of 2,388 families. While we find little evidence for tissue-specific mosaic mutation, multi-tissue post-zygotic mutation (i.e. mosaicism) is frequent, with detectable mosaic variation comprising 5.4% of all de novo mutations. We identify three mosaic missense and likely-gene disrupting mutations in genes previously implicated in ASD (KMT2C, NCKAP1, and MYH10) in probands but none in siblings. We find a strong ascertainment bias for mosaic mutations in probands relative to their unaffected siblings (p = 0.003). We build a model of de novo variation incorporating mosaic variants and errors in classification of mosaic status and from this model we estimate that 33% of mosaic mutations in probands contribute to 5.1% of simplex ASD diagnoses (95% credible interval 1.3% to 8.9%). Our results indicate a contributory role for multi-tissue mosaic mutation in some individuals with an ASD diagnosis.
authors.affiliation: Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, Kennedy Krieger Institute, Maryland, United States of America.
authors.forename: Donald
authors.initials: D
authors.lastname: Freed
authors.affiliation: Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, Kennedy Krieger Institute, Maryland, United States of America.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pevsner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D024501:Nonmuscle Myosin Type IIB / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D035781:Siblings
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; C484362:NCKAP1 protein, human; D009363:Neoplasm Proteins; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains