Primary mitochondrial disorders and mimics: Insights from a large French cohort

Cécile Rouzier (1, 2) , Emmanuelle Pion (3) , Annabelle Chaussenot (1, 2) , Céline Bris (4, 5) , Samira Ait-El-Mkadem Saadi (1, 2) , Valérie Desquiret-Dumas (4, 5) , Naïg Gueguen (4, 5) , Konstantina Fragaki (1, 2) , Patrizia Amati-Bonneau (4, 5) , Giulia Barcia (6, 7, 8) , Pauline Gaignard (9) , Julie Steffann (7, 6, 8) , Alessandra Pennisi (7, 6, 8) , Jean‐paul Bonnefont (7, 6, 8) , Elise Lebigot (9) , Sylvie Bannwarth (1, 2) , Bruno Francou (1, 2) , Benoit Rucheton (10) , Damien Sternberg (11, 12) , Marie‐laure Martin-Negrier (13) , Aurélien Trimouille (14) , Gaëlle Hardy (15, 16) , Stéphane Allouche (17) , Cécile Acquaviva-Bourdain (18) , Cécile Pagan (18) , Anne‐sophie Lebre (19, 20) , Pascal Reynier (4, 5) , Mireille Cossee (21, 3) , Shahram Attarian (22) , Véronique Paquis-Flucklinger (1, 2) , Vincent Procaccio (4, 5)

1 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
2 CHU Nice - Centre Hospitalier Universitaire de Nice
3 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
4 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
5 CHU Angers - Centre Hospitalier Universitaire d'Angers
6 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
7 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
8 Hôpital Necker - Enfants Malades [AP-HP]
9 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
10 CHU Bordeaux
11 CHU Pitié-Salpêtrière [AP-HP]
12 SU - Sorbonne Université
13 Hôpital Pellegrin
14 CHU de Bordeaux Pellegrin [Bordeaux]
15 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
16 IBP - Institut de Biologie et de Pathologie [CHU Grenoble]
17 Hôpital Côte de Nacre [CHU Caen]
18 GHE - Groupement Hospitalier Lyon-Est
19 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris
20 CHU Reims - Hôpital universitaire Robert Debré [Reims]
21 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
22 TIMONE - Hôpital de la Timone [CHU - APHM]

Objective: The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear‐encoded genes. Methods: Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear‐encoded genes. Results: The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases. Interpretation We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with “possible” PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy.

Domaines: Génétique humaine; Génétique des populations [q-bio.PE]; Endocrinologie et métabolisme

Cécile Rouzier, Emmanuelle Pion, Annabelle Chaussenot, Céline Bris, Samira Ait-El-Mkadem Saadi, et al.. Primary mitochondrial disorders and mimics: Insights from a large French cohort. Annals of Clinical and Translational Neurology, In press, Online ahead of print. ⟨10.1002/acn3.52062⟩. ⟨hal-04569049⟩