An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families.

Raúl Juntas Morales ,Pascale Richard,Reda Zenagui,Dimitri Renard,John Rendu,Guilhem Solé,Valérie Biancalana,Pascal Cintas,Elodie Cosset,Mireille Cossée,Nicolas Leboucq,Delphine Lacourt,Edoardo Malfatti,Marie-Laure Martin Négrier,Blandine Acket,François Rivier,C Thèze ,Claude Cancés ,Caroline Espil,Ulrike Walther‐Louvier ,M Kœnig ,Valérie Rigau ,Corinne Métay ,Kévin Yauy ,Aurélien Perrin,Emmanuelle Uro‐Coste ,André Maues De Paula ,Marie-Christine Arné-Bès ,Henri Pégeot

doi:10.3390/genes12081199

Abstract

Diagnosis of myopathies is challenged by the high genetic heterogeneity and clinical overlap of the various etiologies. We previously reported a Next-Generation Sequencing strategy to identify genetic etiology in patients with undiagnosed Limb-Girdle Muscular Dystrophies, Congenital Myopathies, Congenital Muscular Dystrophies, Distal Myopathies, Myofibrillar Myopathies, and hyperCKemia or effort intolerance, using a large gene panel including genes classically associated with other entry diagnostic categories. In this study, we report the comprehensive clinical-biological strategy used to interpret NGS data in a cohort of 156 pediatric and adult patients, that included Copy Number Variants search, variants filtering and interpretation according to ACMG guidelines, segregation studies, deep phenotyping of patients and relatives, transcripts and protein studies, and multidisciplinary meetings. Genetic etiology was identified in 74 patients, a diagnostic yield (47.4%) similar to previous studies. We identified 18 patients (10%) with causative variants in different genes (ACTA1, RYR1, NEB, TTN, TRIP4, CACNA1S, FLNC, TNNT1, and PAPBN1) that resulted in milder and/or atypical phenotypes, with high intrafamilial variability in some cases. Mild phenotypes could mostly be explained by a less deleterious effect of variants on the protein. Detection of inter-individual variability and atypical phenotype-genotype associations is essential for precision medicine, patient care, and to progress in the understanding of the molecular mechanisms of myopathies.

Highlights

Inherited myopathies are clinically and genetically heterogeneous diseases, with 13 clinical and/or histological entry diagnosis groups reported in the Gene Table of Neuromuscular Disorders, [1] More than 200 genes are implicated including the giant and complex titin (TTN) and nebulin (NEB)genes
We identified a pathogenic variant in the RYR1 gene in two siblings (I152 and his sister) with the typical Limb-Girdle Muscular Dystrophies (LGMD) phenotype
Our integrated clinical-biological approach to analyze Next-generation sequencing (NGS) data in a cohort of 156 patients with genetically unclassified myopathies allowed the identification of the genetic defect in 46.7% of patients, and to reveal interindividual variability and atypical phenotypegenotype associations

Summary

Introduction

Inherited myopathies are clinically and genetically heterogeneous diseases, with 13 clinical and/or histological entry diagnosis groups reported in the Gene Table of Neuromuscular Disorders, (http://www.musclegenetable.fr, accept on 9 July 2021) [1] More than 200 genes are implicated including the giant and complex titin (TTN) and nebulin (NEB). The boundaries of the phenotypic entries reported in the classification of myopathies are becoming increasingly ambiguous [2]. Previous NGS studies in muscle diseases showed a variable rate of genetic diagnosis, ranging from 30 to 50% [3,4,5,6,7,8], depending on the number of genes included in the panel and the myopathy classification criteria.

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Conclusion