Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity

Abstract Variant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system (“EVIDENCE”) to analyze SNHL patient data and asse...

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Autores principales:	So Young Kim, Seungmin Lee, Go Hun Seo, Bong Jik Kim, Doo Yi Oh, Jin Hee Han, Moo Kyun Park, So min Lee, Bonggi Kim, Nayoung Yi, Namju Justin Kim, Doo Hyun Koh, Sohyun Hwang, Changwon Keum, Byung Yoon Choi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/debc16281735427387c11105f50bd90f
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spelling	oai:doaj.org-article:debc16281735427387c11105f50bd90f2021-12-02T17:17:39ZPowerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity10.1038/s41598-021-99007-32045-2322https://doaj.org/article/debc16281735427387c11105f50bd90f2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-99007-3https://doaj.org/toc/2045-2322Abstract Variant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system (“EVIDENCE”) to analyze SNHL patient data and assess its diagnostic accuracy. We performed ES of 263 probands manifesting mild to moderate or higher degrees of SNHL. Candidate variants were classified according to the 2015 American College of Medical Genetics guidelines, and we compared the accuracy, call rates, and efficiency of variant prioritizations performed manually by humans or using EVIDENCE. In our in silico panel, 21 synthetic cases were successfully analyzed by EVIDENCE. In our cohort, the ES diagnostic yield for SNHL by manual analysis was 50.19% (132/263) and 50.95% (134/263) by EVIDENCE. EVIDENCE processed ES data 24-fold faster than humans, and the concordant call rate between humans and EVIDENCE was 97.72% (257/263). Additionally, EVIDENCE outperformed human accuracy, especially at discovering causative variants of rare syndromic deafness, whereas flexible interpretations that required predefined specific genotype–phenotype correlations were possible only by manual prioritization. The automated variant prioritization system remarkably facilitated the molecular diagnosis of hearing loss with high accuracy and efficiency, fostering the popularization of molecular genetic diagnosis of SNHL.So Young KimSeungmin LeeGo Hun SeoBong Jik KimDoo Yi OhJin Hee HanMoo Kyun ParkSo min LeeBonggi KimNayoung YiNamju Justin KimDoo Hyun KohSohyun HwangChangwon KeumByung Yoon ChoiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q So Young Kim Seungmin Lee Go Hun Seo Bong Jik Kim Doo Yi Oh Jin Hee Han Moo Kyun Park So min Lee Bonggi Kim Nayoung Yi Namju Justin Kim Doo Hyun Koh Sohyun Hwang Changwon Keum Byung Yoon Choi Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity
description	Abstract Variant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system (“EVIDENCE”) to analyze SNHL patient data and assess its diagnostic accuracy. We performed ES of 263 probands manifesting mild to moderate or higher degrees of SNHL. Candidate variants were classified according to the 2015 American College of Medical Genetics guidelines, and we compared the accuracy, call rates, and efficiency of variant prioritizations performed manually by humans or using EVIDENCE. In our in silico panel, 21 synthetic cases were successfully analyzed by EVIDENCE. In our cohort, the ES diagnostic yield for SNHL by manual analysis was 50.19% (132/263) and 50.95% (134/263) by EVIDENCE. EVIDENCE processed ES data 24-fold faster than humans, and the concordant call rate between humans and EVIDENCE was 97.72% (257/263). Additionally, EVIDENCE outperformed human accuracy, especially at discovering causative variants of rare syndromic deafness, whereas flexible interpretations that required predefined specific genotype–phenotype correlations were possible only by manual prioritization. The automated variant prioritization system remarkably facilitated the molecular diagnosis of hearing loss with high accuracy and efficiency, fostering the popularization of molecular genetic diagnosis of SNHL.
format	article
author	So Young Kim Seungmin Lee Go Hun Seo Bong Jik Kim Doo Yi Oh Jin Hee Han Moo Kyun Park So min Lee Bonggi Kim Nayoung Yi Namju Justin Kim Doo Hyun Koh Sohyun Hwang Changwon Keum Byung Yoon Choi
author_facet	So Young Kim Seungmin Lee Go Hun Seo Bong Jik Kim Doo Yi Oh Jin Hee Han Moo Kyun Park So min Lee Bonggi Kim Nayoung Yi Namju Justin Kim Doo Hyun Koh Sohyun Hwang Changwon Keum Byung Yoon Choi
author_sort	So Young Kim
title	Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity
title_short	Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity
title_full	Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity
title_fullStr	Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity
title_full_unstemmed	Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity
title_sort	powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/debc16281735427387c11105f50bd90f
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Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity

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