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Autism Spectrum Disorder (ASD) is genetically complex, but specific copy number variants (CNVs; e.g., 1q21.1, 16p11.2) and genes (e.g., NRXN1, NLGN4) have been identified as penetrant susceptibility factors, and all of these demonstrate pleiotropy. Many ASD-associated CNVs are, in fact, genomic disorder loci where flanking segmental duplications lead to recurrent deletion and duplication events of the same region in unrelated individuals, but these lesions are large and involve multiple genes. To identify opportunities to establish a more specific genotype and phenotype correlation in ASD, we searched genomic data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 17 individuals from 15 unrelated families carrying a heterozygous guanine duplication (rs797044936; NM_033517.1; c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (at genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (6/7,521 or 0.08% of ASD-affected individuals studied by whole genome sequencing carried the p.Ala1227Glyfs*69 variant). This variant, which is predicted to cause a frameshift leading to a premature stop codon truncating the C-terminal region of the corresponding protein, was not reproducibly found in any of the control groups we analyzed. All probands identified carried de novo mutations with the exception of five individuals in three families who inherited it through somatic mosaicism. This same heterozygous variant in published mouse models leads to an ASD-like phenotype. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (16/16) formally tested for ASD carried a diagnosis, there was variable expression of core ASD features both within families and between families, underscoring the impact of as yet unknown modifiable factors affecting expressivity in autism.

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