Dataset Information

Whole-Exome Sequencing Identifies Damaging de novo Variants in Anencephalic Cases.

ABSTRACT: Background:Anencephaly is a lethal neural tube defect (NTD). Although variants in several genes have been implicated in the development of anencephaly, a more complete picture of variants in the genome, especially de novo variants (DNVs), remains unresolved. We aim to identify DNVs that play an important role in the development of anencephaly by performing whole-exome DNA sequencing (WES) of proband-parent trios. Results:A total of 13 DNVs were identified in 8 anencephaly trios by WES, including two loss of function (LoF) variants detected in pLI > 0.9 genes (SPHKAP, c.2629_2633del, and NCOR1, p.Y1907X). Damaging DNVs were identified in 61.5% (8/13) of the anencephalic cases. Independent validation was conducted in an additional 502 NTD cases. Gene inactivation using targeted morpholino antisense oligomers and rescue assays were conducted in zebrafish, and transfection expression in HEK293T cells. Four DNVs in four cases were identified and predicted to alter protein function, including p.R328Q in WD repeat domain phosphoinositide-interacting 1 (WIPI1). Three variants, p.G313R, p.T418M, and p.L406P, in the WIPI1 gene were identified from the independent replication cohort consisting of 502 cases. Functional analysis suggested that the wipi1 p.L406P and p.R328Q variants most likely displayed loss-of-function effects during embryonic development. Conclusion:De novo damaging variants are the main culprit for majority of anencephalic cases. Missense variants in WIPI1 may play a role in the genetic etiology of anencephaly, and LoF variants in SPHKAP and NCOR1 may also contribute to anencephaly. These findings add to our existing understanding of the genetic mechanisms of NTD formation.

SUBMITTER: Wang L

PROVIDER: S-EPMC6896715 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Whole-Exome Sequencing Identifies Damaging <i>de novo</i> Variants in Anencephalic Cases.

Wang Linlin L Ren Aiguo A Tian Tian T Li Nan N Cao Xuanye X Zhang Peng P Jin Lei L Li Zhiwen Z Shen Yan Y Zhang Bo B Finnell Richard H RH Lei Yunping Y

Frontiers in neuroscience 20191129

<h4>Background</h4>Anencephaly is a lethal neural tube defect (NTD). Although variants in several genes have been implicated in the development of anencephaly, a more complete picture of variants in the genome, especially <i>de novo</i> variants (DNVs), remains unresolved. We aim to identify DNVs that play an important role in the development of anencephaly by performing whole-exome DNA sequencing (WES) of proband-parent trios.<h4>Results</h4>A total of 13 DNVs were identified in 8 anencephaly t ...[more]

PMID: 31849593

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Project description:Autism spectrum disorder (ASD) is a highly heritable condition caused by a combination of environmental and genetic factors such as de novo and inherited variants, as well as rare or common variants among hundreds of related genes. Previous genome-wide association studies have identified susceptibility genes; however, most ASD-associated genes remain undiscovered. This study aimed to examine rare de novo variants to identify genetic risk factors of ASD using whole exome sequencing (WES), functional characterization, and genetic network analyses of identified variants using Korean familial dataset. We recruited children with ASD and their biological parents. The clinical best estimate diagnosis of ASD was made according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5TM), using comprehensive diagnostic instruments. The final analyses included a total of 151 individuals from 51 families. Variants were identified and filtered using the GATK Best Practices for bioinformatics analysis, followed by genome alignments and annotation to the reference genome assembly GRCh37 (liftover to GRCh38), and further annotated using dbSNP 154 build databases. To evaluate allele frequencies of de novo variants, we used the dbSNP, gnomAD exome v2.1.1, and genome v3.0. We used Ingenuity Pathway Analysis (IPA, Qiagen) software to construct networks using all identified de novo variants with known autism-related genes to find probable relationships. We identified 36 de novo variants with potential relations to ASD; 27 missense, two silent, one nonsense, one splice region, one splice site, one 5' UTR, and one intronic SNV and two frameshift deletions. We identified six networks with functional relationships. Among the interactions between de novo variants, the IPA assay found that the NF-κB signaling pathway and its interacting genes were commonly observed at two networks. The relatively small cohort size may affect the results of novel ASD genes with de novo variants described in our findings. We did not conduct functional experiments in this study. Because of the diversity and heterogeneity of ASD, the primary purpose of this study was to investigate probable causative relationships between novel de novo variants and known autism genes. Additionally, we based functional relationships with known genes on network analysis rather than on statistical analysis. We identified new variants that may underlie genetic factors contributing to ASD in Korean families using WES and genetic network analyses. We observed novel de novo variants that might be functionally linked to ASD, of which the variants interact with six genetic networks.

Dataset Information

Whole-Exome Sequencing Identifies Damaging de novo Variants in Anencephalic Cases.

Publications

Whole-Exome Sequencing Identifies Damaging <i>de novo</i> Variants in Anencephalic Cases.

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