Dataset Information

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.

ABSTRACT: We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

SUBMITTER: Lim ET

PROVIDER: S-EPMC5672813 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.

Lim Elaine T ET Uddin Mohammed M De Rubeis Silvia S Chan Yingleong Y Kamumbu Anne S AS Zhang Xiaochang X D'Gama Alissa M AM Kim Sonia N SN Hill Robert Sean RS Goldberg Arthur P AP Poultney Christopher C Minshew Nancy J NJ Kushima Itaru I Aleksic Branko B Ozaki Norio N Parellada Mara M Arango Celso C Penzol Maria J MJ Carracedo Angel A Kolevzon Alexander A Hultman Christina M CM Weiss Lauren A LA Fromer Menachem M Chiocchetti Andreas G AG Freitag Christine M CM Church George M GM Scherer Stephen W SW Buxbaum Joseph D JD Walsh Christopher A CA

Nature neuroscience 20170717 9

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than con ...[more]

PMID: 28714951

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Project description:DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

Dataset Information

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.

Publications

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.

Similar Datasets

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