Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Elsevier Science full text link Elsevier Science Free PMC article
Full text links

Actions

Share

.2013 Aug 8;93(2):249-63.
doi: 10.1016/j.ajhg.2013.06.012. Epub 2013 Jul 11.

Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing

Affiliations

Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing

Yong-hui Jiang et al. Am J Hum Genet..

Abstract

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Detection and Classification of Medically Relevant Genetic Variants Rare SNV and indel variants were assessed as putative etiologic factors in ASD. Samples were also run on high-resolution microarray for CNV calling as indicated in the Material and Methods. Dashed arrows indicate variants not included in downstream analyses. In addition to applying random forests (RF) algorithms and filtering methods, we used Sanger sequencing to perform a manual assessment of potential de novo variants annotated by GATK.aLow-quality variants were eliminated with GATK’s filters.bRare variants were defined as those not found in dbSNP or the 1000 Genomes Project. Each gene bearing rare deleterious variants was classified as (1) a "known" (also called "linked") ASD gene if it was previously identified to be involved in ASD, according to lists developed by the Autism Genome Project Consortium, (2) an "unrecognized" ASD gene if it was not previously recognized to carry a loss-of-function mutation (nonsense, splice site, or frameshift) and if it showed an ASD-related phenotype, as reported in OMIM and/or the MGI mouse knockout database, or (3) a "candidate" ASD gene if it was affected by a de novo deleterious variant. In the case of rare inherited X-linked deleterious variants found in males, the same gene also needed to be implicated in other sequencing studies. Abbreviations are as follows: GATK, Genome Analysis Toolkit; BWA, Burrows-Wheeler Aligner; and segdup, segmental duplication
Figure 2
Figure 2
Correlation between Number of De Novo Mutations and Parental Ages The total number of de novo mutations (DNMs) in the proband was plotted against the age of (A) the father and (B) the mother. The number of mutations increases with the age of the father (p = 0.0045) at a rate of 1.5 de novo mutations per year (slope).
Figure 3
Figure 3
Pedigrees of Families with ASD-Relevant Genetic Variants (A–F) Families with de novo deleterious variants as potential causal events. (G–P) Families with inherited deleterious variants as potential causes of ASD (the sibling in Family A was also found to be a mutation carrier, suggesting gonadal mosaicism). The de novo or inherited variant alleles are shown below each family member. “+” indicates the allele containing the reference (presumably wild-type) sequence (“+/+” for genes on the autosomal chromosome or the X chromosome in female; “+” for genes on the X chromosome in male). Males are denoted by squares and females by circles. Symbols with no inside number indicate that no DNA sample was available for testing. Black symbols indicate individuals diagnosed with ASD. Individual 2-1269-03 (dark gray symbol) was diagnosed with Asperger disorder in adulthood. Symbols filled in light gray (2-1186-04 [A; II-2] and 2-1116-04 [M; II-1]) denote individuals with subclinical features of ASD. As discussed in the Results, individual 2-1269-04 (G; III-2) was also reported by the parents to exhibit autistic-like behavior, and a full ASD evaluation is ongoing. Open symbols denote unaffected individuals, according to currently available information, but status for some may change upon retrospective evaluation. Arrows indicate ASD probands in each family.
Figure 4
Figure 4
Sequencing Coverage in Exonic Regions (A) Comparison of sequencing depth in autosomal exonic regions. (B) Comparison of sequencing read distribution in autosomal exonic regions. (C) Comparison of sequencing depth in X chromosome exonic regions. (D) Comparison of sequencing read distribution in X chromosome exonic regions. WGS captured (A) 10.8% more annotated exons (2.7% more coding) in autosomes and (C) 17.5% more annotated exons (5.7% more coding) in the X chromosome with coverage >5x than WES did. WGS also showed a more uniform capturing of coding regions than WES (B and D).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Scherer S.W., Dawson G. Risk factors for autism: translating genomic discoveries into diagnostics. Hum. Genet. 2011;130:123–148. - PubMed
    1. Carter M.T., Scherer S.W. Autism spectrum disorder in the genetics clinic: a review. Clin. Genet. 2013;83:399–407. - PubMed
    1. Betancur C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2011;1380:42–77. - PubMed
    1. Tuchman R., Cuccaro M. Epilepsy and autism: neurodevelopmental perspective. Curr. Neurol. Neurosci. Rep. 2011;11:428–434. - PubMed
    1. Devlin B., Scherer S.W. Genetic architecture in autism spectrum disorder. Curr. Opin. Genet. Dev. 2012;22:229–237. - PubMed

Publication types

MeSH terms

Related information

Grants and funding

LinkOut - more resources

Full text links
Elsevier Science full text link Elsevier Science Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp