Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries

Abstract Background Defects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1‐related myopathies (RYR1‐RM); the most common subgroup of congenital myopathies. Methods Congenital myopathy presents a diagnostic challenge due to the need for multiple testing modalities to identify the ma...

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Autores principales:	Amelle Shillington, Alonso Zea Vera, Tanya Perry, Robert Hopkin, Cameron Thomas, David Cooper, Kristen Suhrie
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	intronic variants myopathy RNA sequencing RYR1 whole‐genome sequencing Genetics QH426-470
Acceso en línea:	https://doaj.org/article/591293b797094854879f0af6d396af3c
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spelling	oai:doaj.org-article:591293b797094854879f0af6d396af3c2021-11-10T16:39:24ZClinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries2324-926910.1002/mgg3.1804https://doaj.org/article/591293b797094854879f0af6d396af3c2021-10-01T00:00:00Zhttps://doi.org/10.1002/mgg3.1804https://doaj.org/toc/2324-9269Abstract Background Defects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1‐related myopathies (RYR1‐RM); the most common subgroup of congenital myopathies. Methods Congenital myopathy presents a diagnostic challenge due to the need for multiple testing modalities to identify the many different genetic etiologies. In this case, the patient remained undiagnosed after whole‐exome sequencing (WES), chromosomal microarray, methylation analysis, targeted deletion and duplication studies, and targeted repeat expansion studies. Clinical whole‐genome sequencing (WGS) was then pursued as part of a research study to identify a diagnosis. Results WGS identified compound heterozygous RYR1 intronic variants, RNA sequencing confirmed both variants to be pathogenic causing RYR1‐RM in a phenotype of severe congenital hypotonia with respiratory failure from birth, neonatal brain hemorrhage, and congenital heart disease involving transposition of the great arteries. Conclusion While there is an ongoing debate about the clinical superiority of WGS versus WES for patients with a suspected genetic condition, this scenario highlights a weakness of WES as well as the added cost and delay in diagnosis timing with having WGS follow WES or even ending further genetic testing with a negative WES. While knowledge gaps still exist for many intronic variants, transcriptome analysis provides a way of validating the resulting dysfunction caused by these variants and thus allowing for appropriate pathogenicity classification. This is the second published case report of a patient with pathogenic intronic variants in RYR1‐RM, with clinical RNA testing confirming variant pathogenicity and therefore the diagnosis suggesting that for some patients careful analysis of a patient's genome and transcriptome are required for a complete genetic evaluation. The diagnostic odyssey experienced by this patient highlights the importance of early, rapid WGS.Amelle ShillingtonAlonso Zea VeraTanya PerryRobert HopkinCameron ThomasDavid CooperKristen SuhrieWileyarticleintronic variantsmyopathyRNA sequencingRYR1whole‐genome sequencingGeneticsQH426-470ENMolecular Genetics & Genomic Medicine, Vol 9, Iss 10, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	intronic variants myopathy RNA sequencing RYR1 whole‐genome sequencing Genetics QH426-470
spellingShingle	intronic variants myopathy RNA sequencing RYR1 whole‐genome sequencing Genetics QH426-470 Amelle Shillington Alonso Zea Vera Tanya Perry Robert Hopkin Cameron Thomas David Cooper Kristen Suhrie Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries
description	Abstract Background Defects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1‐related myopathies (RYR1‐RM); the most common subgroup of congenital myopathies. Methods Congenital myopathy presents a diagnostic challenge due to the need for multiple testing modalities to identify the many different genetic etiologies. In this case, the patient remained undiagnosed after whole‐exome sequencing (WES), chromosomal microarray, methylation analysis, targeted deletion and duplication studies, and targeted repeat expansion studies. Clinical whole‐genome sequencing (WGS) was then pursued as part of a research study to identify a diagnosis. Results WGS identified compound heterozygous RYR1 intronic variants, RNA sequencing confirmed both variants to be pathogenic causing RYR1‐RM in a phenotype of severe congenital hypotonia with respiratory failure from birth, neonatal brain hemorrhage, and congenital heart disease involving transposition of the great arteries. Conclusion While there is an ongoing debate about the clinical superiority of WGS versus WES for patients with a suspected genetic condition, this scenario highlights a weakness of WES as well as the added cost and delay in diagnosis timing with having WGS follow WES or even ending further genetic testing with a negative WES. While knowledge gaps still exist for many intronic variants, transcriptome analysis provides a way of validating the resulting dysfunction caused by these variants and thus allowing for appropriate pathogenicity classification. This is the second published case report of a patient with pathogenic intronic variants in RYR1‐RM, with clinical RNA testing confirming variant pathogenicity and therefore the diagnosis suggesting that for some patients careful analysis of a patient's genome and transcriptome are required for a complete genetic evaluation. The diagnostic odyssey experienced by this patient highlights the importance of early, rapid WGS.
format	article
author	Amelle Shillington Alonso Zea Vera Tanya Perry Robert Hopkin Cameron Thomas David Cooper Kristen Suhrie
author_facet	Amelle Shillington Alonso Zea Vera Tanya Perry Robert Hopkin Cameron Thomas David Cooper Kristen Suhrie
author_sort	Amelle Shillington
title	Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries
title_short	Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries
title_full	Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries
title_fullStr	Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries
title_full_unstemmed	Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries
title_sort	clinical rna sequencing confirms compound heterozygous intronic variants in ryr1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/591293b797094854879f0af6d396af3c
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Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d‐transposition of the great arteries

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