An Integrated Diagnosis Strategy for Congenital Myopathies

Congenital myopathies are severe muscle disorders affecting adults as well as children in all populations. The diagnosis of congenital myopathies is constrained by strong clinical and genetic heterogeneity. Moreover, the majority of patients present with unspecific histological features, precluding...

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Main Authors:	Böhm, Johann, Vasli, Nasim, Malfatti, Edoardo, Le Gras, Stéphanie, Feger, Claire, Jost, Bernard, Monnier, Nicole, Brocard, Julie, Karasoy, Hatice, Gérard, Marion, Walter, Maggie C., Reilich, Peter, Biancalana, Valérie, Kretz, Christine, Messaddeq, Nadia, Marty, Isabelle, Lunardi, Joël, Romero, Norma B., Laporte, Jocelyn
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691193/

id	pubmed-3691193
recordtype	oai_dc
spelling	pubmed-36911932013-07-03 An Integrated Diagnosis Strategy for Congenital Myopathies Böhm, Johann Vasli, Nasim Malfatti, Edoardo Le Gras, Stéphanie Feger, Claire Jost, Bernard Monnier, Nicole Brocard, Julie Karasoy, Hatice Gérard, Marion Walter, Maggie C. Reilich, Peter Biancalana, Valérie Kretz, Christine Messaddeq, Nadia Marty, Isabelle Lunardi, Joël Romero, Norma B. Laporte, Jocelyn Research Article Congenital myopathies are severe muscle disorders affecting adults as well as children in all populations. The diagnosis of congenital myopathies is constrained by strong clinical and genetic heterogeneity. Moreover, the majority of patients present with unspecific histological features, precluding purposive molecular diagnosis and demonstrating the need for an alternative and more efficient diagnostic approach. We used exome sequencing complemented by histological and ultrastructural analysis of muscle biopsies to identify the causative mutations in eight patients with clinically different skeletal muscle pathologies, ranging from a fatal neonatal myopathy to a mild and slowly progressive myopathy with adult onset. We identified RYR1 (ryanodine receptor) mutations in six patients and NEB (nebulin) mutations in two patients. We found novel missense and nonsense mutations, unraveled small insertions/deletions and confirmed their impact on splicing and mRNA/protein stability. Histological and ultrastructural findings of the muscle biopsies of the patients validated the exome sequencing results. We provide the evidence that an integrated strategy combining exome sequencing with clinical and histopathological investigations overcomes the limitations of the individual approaches to allow a fast and efficient diagnosis, accelerating the patient’s access to a better healthcare and disease management. This is of particular interest for the diagnosis of congenital myopathies, which involve very large genes like RYR1 and NEB as well as genetic and phenotypic heterogeneity. Public Library of Science 2013-06-24 /pmc/articles/PMC3691193/ /pubmed/23826317 http://dx.doi.org/10.1371/journal.pone.0067527 Text en © 2013 Böhm 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	Böhm, Johann Vasli, Nasim Malfatti, Edoardo Le Gras, Stéphanie Feger, Claire Jost, Bernard Monnier, Nicole Brocard, Julie Karasoy, Hatice Gérard, Marion Walter, Maggie C. Reilich, Peter Biancalana, Valérie Kretz, Christine Messaddeq, Nadia Marty, Isabelle Lunardi, Joël Romero, Norma B. Laporte, Jocelyn
spellingShingle	Böhm, Johann Vasli, Nasim Malfatti, Edoardo Le Gras, Stéphanie Feger, Claire Jost, Bernard Monnier, Nicole Brocard, Julie Karasoy, Hatice Gérard, Marion Walter, Maggie C. Reilich, Peter Biancalana, Valérie Kretz, Christine Messaddeq, Nadia Marty, Isabelle Lunardi, Joël Romero, Norma B. Laporte, Jocelyn An Integrated Diagnosis Strategy for Congenital Myopathies
author_facet	Böhm, Johann Vasli, Nasim Malfatti, Edoardo Le Gras, Stéphanie Feger, Claire Jost, Bernard Monnier, Nicole Brocard, Julie Karasoy, Hatice Gérard, Marion Walter, Maggie C. Reilich, Peter Biancalana, Valérie Kretz, Christine Messaddeq, Nadia Marty, Isabelle Lunardi, Joël Romero, Norma B. Laporte, Jocelyn
author_sort	Böhm, Johann
title	An Integrated Diagnosis Strategy for Congenital Myopathies
title_short	An Integrated Diagnosis Strategy for Congenital Myopathies
title_full	An Integrated Diagnosis Strategy for Congenital Myopathies
title_fullStr	An Integrated Diagnosis Strategy for Congenital Myopathies
title_full_unstemmed	An Integrated Diagnosis Strategy for Congenital Myopathies
title_sort	integrated diagnosis strategy for congenital myopathies
description	Congenital myopathies are severe muscle disorders affecting adults as well as children in all populations. The diagnosis of congenital myopathies is constrained by strong clinical and genetic heterogeneity. Moreover, the majority of patients present with unspecific histological features, precluding purposive molecular diagnosis and demonstrating the need for an alternative and more efficient diagnostic approach. We used exome sequencing complemented by histological and ultrastructural analysis of muscle biopsies to identify the causative mutations in eight patients with clinically different skeletal muscle pathologies, ranging from a fatal neonatal myopathy to a mild and slowly progressive myopathy with adult onset. We identified RYR1 (ryanodine receptor) mutations in six patients and NEB (nebulin) mutations in two patients. We found novel missense and nonsense mutations, unraveled small insertions/deletions and confirmed their impact on splicing and mRNA/protein stability. Histological and ultrastructural findings of the muscle biopsies of the patients validated the exome sequencing results. We provide the evidence that an integrated strategy combining exome sequencing with clinical and histopathological investigations overcomes the limitations of the individual approaches to allow a fast and efficient diagnosis, accelerating the patient’s access to a better healthcare and disease management. This is of particular interest for the diagnosis of congenital myopathies, which involve very large genes like RYR1 and NEB as well as genetic and phenotypic heterogeneity.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691193/
_version_	1611988989298868224

An Integrated Diagnosis Strategy for Congenital Myopathies

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