Dataset Information

Frequency and signature of somatic variants in 1461 human brain exomes.

ABSTRACT:

Purpose

To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders.

Methods

In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum. Identified somatic variants were validated by targeted amplicon sequencing and/or PyroMark® Q24.

Results

We observed somatic coding variants present in >10% of sampled cells in at least 1% of brains. The mutational signature of the detected variants showed a predominance of C>T variants most consistent with arising from DNA mismatch repair, occurred frequently in genes that are highly expressed within the central nervous system, and with a minimum somatic mutation rate of 4.25 × 10^-10 per base pair per individual.

Conclusion

These findings provide proof-of-principle that deleterious somatic variants can affect sizeable brain regions in at least 1% of the population, and thus have the potential to contribute to the pathogenesis of common neurodegenerative diseases.

SUBMITTER: Wei W

PROVIDER: S-EPMC6544539 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Frequency and signature of somatic variants in 1461 human brain exomes.

Wei Wei W Keogh Michael J MJ Aryaman Juvid J Golder Zoe Z Kullar Peter J PJ Wilson Ian I Talbot Kevin K Turner Martin R MR McKenzie Chris-Anne CA Troakes Claire C Attems Johannes J Smith Colin C Sarraj Safa Al SA Morris Chris M CM Ansorge Olaf O Jones Nick S NS Ironside James W JW Chinnery Patrick F PF

Genetics in medicine : official journal of the American College of Medical Genetics 20180914 4

<h4>Purpose</h4>To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders.<h4>Methods</h4>In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum. Identified somatic variants were validated by targeted amplicon sequencing and/or PyroMark® Q24.<h4>Results</h4>We obse ...[more]

PMID: 30214067

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Project description:ImportanceDiagnostic genetic testing can lead to changes in management in the pediatric intensive care unit. Genetic risk in children with critical illness but nondiagnostic exome sequencing (ES) has not been explored.ObjectiveTo assess the association between loss-of-function (LOF) variants and pediatric critical illness.Design, setting, and participantsThis genetic association study examined ES first screened for causative variants among 267 children at the Morgan Stanley Children's Hospital of NewYork-Presbyterian, of whom 22 were otherwise healthy with viral respiratory failure; 18 deceased children with bronchiolitis from the Office of the Chief Medical Examiner of New York City, of whom 14 were previously healthy; and 9990 controls from the Institute for Genomic Medicine at Columbia University Irving Medical Center. The ES data were generated between January 1, 2015, and December 31, 2020, and analyzed between January 1, 2017, and September 2, 2022.ExposureCritical illness.Main outcomes and measuresOdds ratios and P values for genes and gene-sets enriched for rare LOF variants and the loss-of-function observed/expected upper bound fraction (LOEUF) score at which cases have a significant enrichment.ResultsThis study included 285 children with critical illness (median [range] age, 4.1 [0-18.9] years; 148 [52%] male) and 9990 controls. A total of 228 children (80%) did not receive a genetic diagnosis. After quality control (QC), 231 children harbored excess rare LOF variants in genes with a LOEUF score of 0.680 or less (intolerant genes) (P = 1.0 × 10-5). After QC, 176 children without a diagnosis harbored excess ultrarare LOF variants in intolerant genes but only in those without a known disease association (odds ratio, 1.8; 95% CI, 1.3-2.5). After QC, 25 children with viral respiratory failure harbored excess ultrarare LOF variants in intolerant genes but only in those without a known disease association (odds ratio, 2.8; 95% CI, 1.1-6.6). A total of 114 undiagnosed children were enriched for de novo LOF variants in genes without a known disease association (observed, 14; expected, 6.8; enrichment, 2.05).Conclusions and relevanceIn this genetic association study, excess LOF variants were observed among critically ill children despite nondiagnostic ES. Variants lay in genes without a known disease association, suggesting future investigation may connect phenotypes to causative genes.

Dataset Information

Frequency and signature of somatic variants in 1461 human brain exomes.

Purpose

Methods

Results

Conclusion

Publications

Frequency and signature of somatic variants in 1461 human brain exomes.

Similar Datasets

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