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

• Published in: Genes Vol. 12; no. 8; p. 1199
• Main Authors: Juntas Morales, Raul, Perrin, Aurélien, Solé, Guilhem, Lacourt, Delphine, Pegeot, Henri, Walther-Louvier, Ulrike, Cintas, Pascal, Cances, Claude, Espil, Caroline, Theze, Corinne, Zenagui, Reda, Yauy, Kevin, Cosset, Elodie, Renard, Dimitri, Rigau, Valerie, Maues de Paula, Andre, Uro-Coste, Emmanuelle, Arne-Bes, Marie-Christine, Martin Négrier, Marie-Laure, Leboucq, Nicolas, Acket, Blandine, Malfatti, Edoardo, Biancalana, Valérie, Metay, Corinne, Richard, Pascale, Rendu, John, Rivier, François, Koenig, Michel, Cossée, Mireille
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31.07.2021; MDPI
• Subjects: Adult; atypical phenotype-genotype associations; Bioinformatics; Biopsy; Child; Cohort Studies; Congenital diseases; Copy number; Creatine kinase; deep phenotyping; Disease; Etiology; Family medical history; Female; Genes; Genetics; Genomics; Genotype; Genotype & phenotype; Genotypes; High-Throughput Nucleotide Sequencing - methods; Hight-Throughput Nucleotide Sequencing; Human genetics; Human health and pathology; Humans; inter-individual variability; Intolerance; Life Sciences; Male; Metabolism; Molecular modelling; Muscular Diseases; Muscular Diseases - diagnosis; Muscular Diseases - genetics; Muscular Diseases - pathology; myopathies; Next-generation sequencing; Patients; Pediatrics; Phenotype; Phenotypes; Phenotyping; Populations and Evolution; Precision medicine; Ryanodine receptors; Serum levels; Software; atypical phenotype-genotype associations; myopathies; deep phenotyping; next generation sequencing; inter-individual variability; Deep phenotyping; Myopathies; Atypical phenotype-genotype associations; Next generation sequencing; Inter-individual variability
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes12081199

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 ( and ) 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.