Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees

The identification of disease-causing mutations in next-generation sequencing (NGS) data requires efficient filtering techniques. In patients with rare recessive diseases, compound heterozygosity of pathogenic mutations is the most likely inheritance model if the parents are non-consanguineous. We d...

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Main Authors:	Kamphans, Tom, Sabri, Peggy, Zhu, Na, Heinrich, Verena, Mundlos, Stefan, Robinson, Peter N., Parkhomchuk, Dmitri, Krawitz, Peter M.
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734130/

id	pubmed-3734130
recordtype	oai_dc
spelling	pubmed-37341302013-08-12 Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees Kamphans, Tom Sabri, Peggy Zhu, Na Heinrich, Verena Mundlos, Stefan Robinson, Peter N. Parkhomchuk, Dmitri Krawitz, Peter M. Research Article The identification of disease-causing mutations in next-generation sequencing (NGS) data requires efficient filtering techniques. In patients with rare recessive diseases, compound heterozygosity of pathogenic mutations is the most likely inheritance model if the parents are non-consanguineous. We developed a web-based compound heterozygous filter that is suited for data from NGS projects and that is easy to use for non-bioinformaticians. We analyzed the power of compound heterozygous mutation filtering by deriving background distributions for healthy individuals from different ethnicities and studied the effectiveness in trios as well as more complex pedigree structures. While usually more then 30 genes harbor potential compound heterozygotes in single exomes, this number can be markedly reduced with every additional member of the pedigree that is included in the analysis. In a real data set with exomes of four family members, two sisters affected by Mabry syndrome and their healthy parents, the disease-causing gene PIGO, which harbors the pathogenic compound heterozygous variants, could be readily identified. Compound heterozygous filtering is an efficient means to reduce the number of candidate mutations in studies aiming at identifying recessive disease genes in non-consanguineous families. A web-server is provided to make this filtering strategy available at www.gene-talk.de. Public Library of Science 2013-08-05 /pmc/articles/PMC3734130/ /pubmed/23940540 http://dx.doi.org/10.1371/journal.pone.0070151 Text en © 2013 Kamphans et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kamphans, Tom Sabri, Peggy Zhu, Na Heinrich, Verena Mundlos, Stefan Robinson, Peter N. Parkhomchuk, Dmitri Krawitz, Peter M.
spellingShingle	Kamphans, Tom Sabri, Peggy Zhu, Na Heinrich, Verena Mundlos, Stefan Robinson, Peter N. Parkhomchuk, Dmitri Krawitz, Peter M. Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees
author_facet	Kamphans, Tom Sabri, Peggy Zhu, Na Heinrich, Verena Mundlos, Stefan Robinson, Peter N. Parkhomchuk, Dmitri Krawitz, Peter M.
author_sort	Kamphans, Tom
title	Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees
title_short	Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees
title_full	Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees
title_fullStr	Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees
title_full_unstemmed	Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees
title_sort	filtering for compound heterozygous sequence variants in non-consanguineous pedigrees
description	The identification of disease-causing mutations in next-generation sequencing (NGS) data requires efficient filtering techniques. In patients with rare recessive diseases, compound heterozygosity of pathogenic mutations is the most likely inheritance model if the parents are non-consanguineous. We developed a web-based compound heterozygous filter that is suited for data from NGS projects and that is easy to use for non-bioinformaticians. We analyzed the power of compound heterozygous mutation filtering by deriving background distributions for healthy individuals from different ethnicities and studied the effectiveness in trios as well as more complex pedigree structures. While usually more then 30 genes harbor potential compound heterozygotes in single exomes, this number can be markedly reduced with every additional member of the pedigree that is included in the analysis. In a real data set with exomes of four family members, two sisters affected by Mabry syndrome and their healthy parents, the disease-causing gene PIGO, which harbors the pathogenic compound heterozygous variants, could be readily identified. Compound heterozygous filtering is an efficient means to reduce the number of candidate mutations in studies aiming at identifying recessive disease genes in non-consanguineous families. A web-server is provided to make this filtering strategy available at www.gene-talk.de.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734130/
_version_	1612000757559590912

Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees

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