Effective variant filtering and expected candidate variant yield in studies of rare human disease

Abstract In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to...

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Autores principales:	Brent S. Pedersen, Joe M. Brown, Harriet Dashnow, Amelia D. Wallace, Matt Velinder, Martin Tristani-Firouzi, Joshua D. Schiffman, Tatiana Tvrdik, Rong Mao, D. Hunter Best, Pinar Bayrak-Toydemir, Aaron R. Quinlan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/709f6f141917434d9d3529666fde6ab7
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spelling	oai:doaj.org-article:709f6f141917434d9d3529666fde6ab72021-12-02T16:08:17ZEffective variant filtering and expected candidate variant yield in studies of rare human disease10.1038/s41525-021-00227-32056-7944https://doaj.org/article/709f6f141917434d9d3529666fde6ab72021-07-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00227-3https://doaj.org/toc/2056-7944Abstract In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.Brent S. PedersenJoe M. BrownHarriet DashnowAmelia D. WallaceMatt VelinderMartin Tristani-FirouziJoshua D. SchiffmanTatiana TvrdikRong MaoD. Hunter BestPinar Bayrak-ToydemirAaron R. QuinlanNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Brent S. Pedersen Joe M. Brown Harriet Dashnow Amelia D. Wallace Matt Velinder Martin Tristani-Firouzi Joshua D. Schiffman Tatiana Tvrdik Rong Mao D. Hunter Best Pinar Bayrak-Toydemir Aaron R. Quinlan Effective variant filtering and expected candidate variant yield in studies of rare human disease
description	Abstract In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.
format	article
author	Brent S. Pedersen Joe M. Brown Harriet Dashnow Amelia D. Wallace Matt Velinder Martin Tristani-Firouzi Joshua D. Schiffman Tatiana Tvrdik Rong Mao D. Hunter Best Pinar Bayrak-Toydemir Aaron R. Quinlan
author_facet	Brent S. Pedersen Joe M. Brown Harriet Dashnow Amelia D. Wallace Matt Velinder Martin Tristani-Firouzi Joshua D. Schiffman Tatiana Tvrdik Rong Mao D. Hunter Best Pinar Bayrak-Toydemir Aaron R. Quinlan
author_sort	Brent S. Pedersen
title	Effective variant filtering and expected candidate variant yield in studies of rare human disease
title_short	Effective variant filtering and expected candidate variant yield in studies of rare human disease
title_full	Effective variant filtering and expected candidate variant yield in studies of rare human disease
title_fullStr	Effective variant filtering and expected candidate variant yield in studies of rare human disease
title_full_unstemmed	Effective variant filtering and expected candidate variant yield in studies of rare human disease
title_sort	effective variant filtering and expected candidate variant yield in studies of rare human disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/709f6f141917434d9d3529666fde6ab7
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Effective variant filtering and expected candidate variant yield in studies of rare human disease

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