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

Raul Juntas Morales (1, 2, 3) , Aurélien Perrin (4, 1) , Guilhem Solé (5) , Delphine Lacourt (1) , Henri Pegeot (1) , Ulrike Walther-Louvier (1) , Pascal Cintas (6) , Claude Cances (6) , Caroline Espil (5) , Corinne Theze (1) , Reda Zenagui (1) , Kevin Yauy (1) , Elodie Cosset (3) , Dimitri Renard (7, 8) , Valerie Rigau (1, 2) , Andre Maues de Paula (9) , Emmanuelle Uro-Coste (6) , Marie-Christine Arne-Bes (6) , Marie-Laure Martin Négrier (10) , Nicolas Leboucq (1) , Blandine Acket (6) , Edoardo Malfatti (11, 12) , Valérie Biancalana (13, 14) , Corinne Metay (15) , Pascale Richard (15, 16) , John Rendu (17, 18) , Francois Rivier (4, 1) , Michel Koenig (4, 1) , Mireille Cossée (4, 1)

1 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
2 INM - Institut des Neurosciences de Montpellier
3 Institut Universitaire de Recherche Clinique
4 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
5 CHU Bordeaux
6 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
7 Pôle NIRR - Service de Neurologie [CHU Nimes]
8 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
9 CHU Marseille
10 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
11 Hôpital Raymond Poincaré [AP-HP]
12 END-ICAP - Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées
13 UNISTRA - Université de Strasbourg
14 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
15 CHU Pitié-Salpêtrière [AP-HP]
16 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
17 GIN - [GIN] Grenoble Institut des Neurosciences
18 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]

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.

Mots clés: Inter-individual variability; Deep phenotyping; Next generation sequencing; Myopathies; Atypical phenotype-genotype associations

Domaines: Génétique humaine; Génétique des populations [q-bio.PE]; Médecine humaine et pathologie

Raul Juntas Morales, Aurélien Perrin, Guilhem Solé, Delphine Lacourt, Henri Pegeot, et al.. An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families. Genes, 2021, 12 (8), pp.1199. ⟨10.3390/genes12081199⟩. ⟨hal-03314914v2⟩