Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases

Abstract Inherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by pathogenic variants in more than 270 genes. As 30–40% of cases remain genetically unexplained following conventional genetic testing, we aimed to obtain a genetic...

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Autores principales:	Zeinab Fadaie, Laura Whelan, Tamar Ben-Yosef, Adrian Dockery, Zelia Corradi, Christian Gilissen, Lonneke Haer-Wigman, Jordi Corominas, Galuh D. N. Astuti, Laura de Rooij, L. Ingeborgh van den Born, Caroline C. W. Klaver, Carel B. Hoyng, Niamh Wynne, Emma S. Duignan, Paul F. Kenna, Frans P. M. Cremers, G. Jane Farrar, Susanne Roosing
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/134ff20611604419a17d57355443d530
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spelling	oai:doaj.org-article:134ff20611604419a17d57355443d5302021-11-21T12:42:51ZWhole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases10.1038/s41525-021-00261-12056-7944https://doaj.org/article/134ff20611604419a17d57355443d5302021-11-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00261-1https://doaj.org/toc/2056-7944Abstract Inherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by pathogenic variants in more than 270 genes. As 30–40% of cases remain genetically unexplained following conventional genetic testing, we aimed to obtain a genetic diagnosis in an IRD cohort in which the genetic cause was not found using whole-exome sequencing or targeted capture sequencing. We performed whole-genome sequencing (WGS) to identify causative variants in 100 unresolved cases. After initial prioritization, we performed an in-depth interrogation of all noncoding and structural variants in genes when one candidate variant was detected. In addition, functional analysis of putative splice-altering variants was performed using in vitro splice assays. We identified the genetic cause of the disease in 24 patients. Causative coding variants were observed in genes such as ATXN7, CEP78, EYS, FAM161A, and HGSNAT. Gene disrupting structural variants were also detected in ATXN7, PRPF31, and RPGRIP1. In 14 monoallelic cases, we prioritized candidate noncanonical splice sites or deep-intronic variants that were predicted to disrupt the splicing process based on in silico analyses. Of these, seven cases were resolved as they carried pathogenic splice defects. WGS is a powerful tool to identify causative variants residing outside coding regions or heterozygous structural variants. This approach was most efficient in cases with a distinct clinical diagnosis. In addition, in vitro splice assays provide important evidence of the pathogenicity of rare variants.Zeinab FadaieLaura WhelanTamar Ben-YosefAdrian DockeryZelia CorradiChristian GilissenLonneke Haer-WigmanJordi CorominasGaluh D. N. AstutiLaura de RooijL. Ingeborgh van den BornCaroline C. W. KlaverCarel B. HoyngNiamh WynneEmma S. DuignanPaul F. KennaFrans P. M. CremersG. Jane FarrarSusanne RoosingNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Zeinab Fadaie Laura Whelan Tamar Ben-Yosef Adrian Dockery Zelia Corradi Christian Gilissen Lonneke Haer-Wigman Jordi Corominas Galuh D. N. Astuti Laura de Rooij L. Ingeborgh van den Born Caroline C. W. Klaver Carel B. Hoyng Niamh Wynne Emma S. Duignan Paul F. Kenna Frans P. M. Cremers G. Jane Farrar Susanne Roosing Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases
description	Abstract Inherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by pathogenic variants in more than 270 genes. As 30–40% of cases remain genetically unexplained following conventional genetic testing, we aimed to obtain a genetic diagnosis in an IRD cohort in which the genetic cause was not found using whole-exome sequencing or targeted capture sequencing. We performed whole-genome sequencing (WGS) to identify causative variants in 100 unresolved cases. After initial prioritization, we performed an in-depth interrogation of all noncoding and structural variants in genes when one candidate variant was detected. In addition, functional analysis of putative splice-altering variants was performed using in vitro splice assays. We identified the genetic cause of the disease in 24 patients. Causative coding variants were observed in genes such as ATXN7, CEP78, EYS, FAM161A, and HGSNAT. Gene disrupting structural variants were also detected in ATXN7, PRPF31, and RPGRIP1. In 14 monoallelic cases, we prioritized candidate noncanonical splice sites or deep-intronic variants that were predicted to disrupt the splicing process based on in silico analyses. Of these, seven cases were resolved as they carried pathogenic splice defects. WGS is a powerful tool to identify causative variants residing outside coding regions or heterozygous structural variants. This approach was most efficient in cases with a distinct clinical diagnosis. In addition, in vitro splice assays provide important evidence of the pathogenicity of rare variants.
format	article
author	Zeinab Fadaie Laura Whelan Tamar Ben-Yosef Adrian Dockery Zelia Corradi Christian Gilissen Lonneke Haer-Wigman Jordi Corominas Galuh D. N. Astuti Laura de Rooij L. Ingeborgh van den Born Caroline C. W. Klaver Carel B. Hoyng Niamh Wynne Emma S. Duignan Paul F. Kenna Frans P. M. Cremers G. Jane Farrar Susanne Roosing
author_facet	Zeinab Fadaie Laura Whelan Tamar Ben-Yosef Adrian Dockery Zelia Corradi Christian Gilissen Lonneke Haer-Wigman Jordi Corominas Galuh D. N. Astuti Laura de Rooij L. Ingeborgh van den Born Caroline C. W. Klaver Carel B. Hoyng Niamh Wynne Emma S. Duignan Paul F. Kenna Frans P. M. Cremers G. Jane Farrar Susanne Roosing
author_sort	Zeinab Fadaie
title	Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases
title_short	Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases
title_full	Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases
title_fullStr	Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases
title_full_unstemmed	Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases
title_sort	whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/134ff20611604419a17d57355443d530
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Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases

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