Whole-genome sequencing identifies frequent mutations of microcephaly-associated genes in autism

来源 :遗传学与表观遗传学前沿暨第三届中国青年遗传学家论坛 | 被引量 : 0次 | 上传用户:wqc851109
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  Autism spectrum disorders (ASD)are neurodevelopmental disorders with substantial clinical and genetic heterogeneity.Recent whole-exome sequencing (WES)and whole-genome sequencing (WGS)studies, which primarily focused on identification of de novo mutations (DNMs) in exonic regions for ASD, suggest that disruptive DNMs contribute to the risk of ASD for about 10-15% of probands.Here, using an integrated model to analyze both de novo and transmitted rare deleterious variants in WGS dataset of 32 Chinese trios with ASD, we identified 87 potentially risk genes (P<0.01) from 4,832 genes harboring various rare deleterious variants, including CHD8 and NRXN2.In particular, frequent rare inherited mutations of several microcephaly-associated genes (ASPM, WDR62, and ZNF335) were found in the Chinese cohort.In ASPM gene, five different predicted deleterious missense mutations were found in six unrelated probands with ASD and intellectual disability (ID).In chromosomal structure analyses, we found a de novo duplicationof UBE3A-containingregion at 15q 11.2-q1 3.1, which causes Angelman syndrome and microcephaly, and a disrupted TNR due to chromosomal rearrangements t(1 ;5)(q25.1 ;q33.2), which is linked to ID.Taken together, our results suggest that abnormalities of centrosomal function and chromatin remodeling of the microcephaly-associated genes are actively implicated in pathogenesis of ASD.
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