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

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Dec;19(12):1300-1308.
doi: 10.1038/gim.2017.50. Epub 2017 May 4.

Assessment of the ExAC data set for the presence of individuals with pathogenic genotypes implicated in severe Mendelian pediatric disorders

Maja Tarailo-Graovac  1   2   3   4 , Jing Yun Alice Zhu  5 , Allison Matthews  1   2   3 , Clara D M van Karnebeek  1   3   6   7 , Wyeth W Wasserman  1   2   3
Affiliations

Assessment of the ExAC data set for the presence of individuals with pathogenic genotypes implicated in severe Mendelian pediatric disorders

Maja Tarailo-Graovac et al. Genet Med. 2017 Dec.

Abstract

PurposeWe analyzed the Exome Aggregation Consortium (ExAC) data set for the presence of individuals with pathogenic genotypes implicated in Mendelian pediatric disorders.MethodsClinVar likely/pathogenic variants supported by at least one peer-reviewed publication were assessed within the ExAC database to identify individuals expected to exhibit a childhood disorder based on concordance with disease inheritance modes: heterozygous (for dominant), homozygous (for recessive) or hemizygous (for X-linked recessive conditions). Variants from 924 genes reported to cause Mendelian childhood disorders were considered.ResultsWe identified ExAC individuals with candidate pathogenic genotypes for 190 previously published likely/pathogenic variants in 128 genes. After curation, we determined that 113 of the variants have sufficient support for pathogenicity and identified 1,717 ExAC individuals (~2.8% of the ExAC population) with corresponding possible/disease-associated genotypes implicated in rare Mendelian disorders, ranging from mild (e.g., due to SCN2A deficiency) to severe pediatric conditions (e.g., due to FGFR1 deficiency).ConclusionLarge-scale sequencing projects and data aggregation consortia provide unprecedented opportunities to determine the prevalence of pathogenic genotypes in unselected populations. This knowledge is crucial for understanding the penetrance of disease-associated variants, phenotypic variability, somatic mosaicism, as well as published literature curation for variant classification procedures and predicted clinical outcomes.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Histogram plot of the number of ExAC individuals with 190 likely/pathogenic variants corresponding to candidate genotypes. This plot shows the distribution of the entire set of 190 variants in terms of the number of ExAC individuals corresponding to each variant (bin size of histogram=30). The y-axis represents the number of variants with number of ExAC individuals equal to the corresponding value on the x-axis. According to the five-number summary of all 190 variants: sample minimum = 1, lower quartile = 1, median = 1, upper quartile = 6, sample maximum = 9,246.
Figure 2
Figure 2
Box plot of the number of ExAC individuals with 190 likely/pathogenic variants grouped according to the number of PMID support. This plot shows distribution of the entire set of 190 variants. The y-axis represents a log10 scale, while the x-axis reflects grouping of the variants based on the level of the published support (PMID=1 vs. PMID>1). Outliers are represented by a dot. It shows that the PMID = 1 group has a higher number of ExAC individuals than the PMID >1 group.
See this image and copyright information in PMC

References

    1. Boycott KM, Vanstone MR, Bulman DE et al, Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat Rev Genet 2013;14:681–691. - PubMed
    1. Yang Y, Muzny DM, Xia F et al, Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014;312:1870–1879. - PMC - PubMed
    1. Tarailo-Graovac M, Shyr C, Ross CJ et al, Exome sequencing and the management of neurometabolic disorders. N Engl J Med 2016;374:2246–2255. - PMC - PubMed
    1. Wenger AM, Guturu H, Bernstein JA et al, Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet Med 2016;19:209–214. - PubMed
    1. Richards S, Aziz N, Bale S et al, Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–423. - PMC - PubMed

Publication types

Grants and funding