Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen

Abstract Autosomal recessive diseases (ARD) are typically caused by a limited number of mutations whose identification is challenged by their low prevalence. Our purpose was to develop a novel approach allowing an efficient search for mutations causing ARD and evaluation of their pathogenicity witho...

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Main Authors:	Urszula Lechowicz, Tomasz Gambin, Agnieszka Pollak, Anna Podgorska, Piotr Stawinski, Andre Franke, Britt-Sabina Petersen, Malgorzata Firczuk, Monika Oldak, Henryk Skarzynski, Rafal Ploski
Format:	Article
Language:	English
Published:	Nature Publishing Group 2017-05-01
Series:	Scientific Reports
Online Access:	https://doi.org/10.1038/s41598-017-02315-w

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spelling	doaj-8bd53056b97f4413bd8fabb621fa592d2020-12-08T00:59:46ZengNature Publishing GroupScientific Reports2045-23222017-05-017111010.1038/s41598-017-02315-wIterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screenUrszula Lechowicz0Tomasz Gambin1Agnieszka Pollak2Anna Podgorska3Piotr Stawinski4Andre Franke5Britt-Sabina Petersen6Malgorzata Firczuk7Monika Oldak8Henryk Skarzynski9Rafal Ploski10Department of Genetics, Institute of Physiology and Pathology of HearingInstitute of Computer Science, Warsaw University of TechnologyDepartment of Genetics, Institute of Physiology and Pathology of HearingDepartment of Genetics, Institute of Physiology and Pathology of HearingDepartment of Genetics, Institute of Physiology and Pathology of HearingInstitute of Clinical Molecular Biology, Kiel UniversityInstitute of Clinical Molecular Biology, Kiel UniversityDepartment of Immunology, Center of Biostructure Research, Medical University of WarsawDepartment of Genetics, Institute of Physiology and Pathology of HearingOto-Rhino-Laryngology Surgery Clinic, Institute of Physiology and Pathology of HearingDepartment of Medical Genetics, Center of Biostructure, Medical University of WarsawAbstract Autosomal recessive diseases (ARD) are typically caused by a limited number of mutations whose identification is challenged by their low prevalence. Our purpose was to develop a novel approach allowing an efficient search for mutations causing ARD and evaluation of their pathogenicity without a control group. We developed Iterative Sequencing and Variant Screening (ISVS) approach based on iterative cycles of gene sequencing and mutation screening, and ISVS Simulator software ( http://zsibio.ii.pw.edu.pl/shiny/isvs/ ) for assessment of detected variants’ significance. As shown by simulations, ISVS efficiently identifies and correctly classifies pathogenic mutations except for cases where the gene of interest has extremely high number of low frequency nonpathogenic variants. By applying ISVS, we found 4 known and 9 novel (p.C73Y, p.S124L, p.C194Mfs17, c.782 + 2 T > A, c.953-5 A > G, p.L325Q, p.D334Mfs24, p.R436G, p.M448T) TMPRSS3 variants among deaf patients. For 3 known and 5 novel variants the disease association was supported by ISVS Simulator odds >90:1. Pathogenicity of 6 novel mutations has been supported by in-silico predictions of variants’ deleteriousness. By directly comparing variant prevalence in patients and controls, disease association was demonstrated only for two variants and it was relatively weak (P < 0.05). Summarizing, ISVS strategy and ISVS Simulator are useful for detection of genetic variants causing AR diseases.https://doi.org/10.1038/s41598-017-02315-w
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Urszula Lechowicz Tomasz Gambin Agnieszka Pollak Anna Podgorska Piotr Stawinski Andre Franke Britt-Sabina Petersen Malgorzata Firczuk Monika Oldak Henryk Skarzynski Rafal Ploski
spellingShingle	Urszula Lechowicz Tomasz Gambin Agnieszka Pollak Anna Podgorska Piotr Stawinski Andre Franke Britt-Sabina Petersen Malgorzata Firczuk Monika Oldak Henryk Skarzynski Rafal Ploski Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen Scientific Reports
author_facet	Urszula Lechowicz Tomasz Gambin Agnieszka Pollak Anna Podgorska Piotr Stawinski Andre Franke Britt-Sabina Petersen Malgorzata Firczuk Monika Oldak Henryk Skarzynski Rafal Ploski
author_sort	Urszula Lechowicz
title	Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen
title_short	Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen
title_full	Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen
title_fullStr	Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen
title_full_unstemmed	Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen
title_sort	iterative sequencing and variant screening (isvs) as a novel pathogenic mutations search strategy - application for tmprss3 mutations screen
publisher	Nature Publishing Group
series	Scientific Reports
issn	2045-2322
publishDate	2017-05-01
description	Abstract Autosomal recessive diseases (ARD) are typically caused by a limited number of mutations whose identification is challenged by their low prevalence. Our purpose was to develop a novel approach allowing an efficient search for mutations causing ARD and evaluation of their pathogenicity without a control group. We developed Iterative Sequencing and Variant Screening (ISVS) approach based on iterative cycles of gene sequencing and mutation screening, and ISVS Simulator software ( http://zsibio.ii.pw.edu.pl/shiny/isvs/ ) for assessment of detected variants’ significance. As shown by simulations, ISVS efficiently identifies and correctly classifies pathogenic mutations except for cases where the gene of interest has extremely high number of low frequency nonpathogenic variants. By applying ISVS, we found 4 known and 9 novel (p.C73Y, p.S124L, p.C194Mfs17, c.782 + 2 T > A, c.953-5 A > G, p.L325Q, p.D334Mfs24, p.R436G, p.M448T) TMPRSS3 variants among deaf patients. For 3 known and 5 novel variants the disease association was supported by ISVS Simulator odds >90:1. Pathogenicity of 6 novel mutations has been supported by in-silico predictions of variants’ deleteriousness. By directly comparing variant prevalence in patients and controls, disease association was demonstrated only for two variants and it was relatively weak (P < 0.05). Summarizing, ISVS strategy and ISVS Simulator are useful for detection of genetic variants causing AR diseases.
url	https://doi.org/10.1038/s41598-017-02315-w
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Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen

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