Genome sequencing improves diagnostic outcomes over panel and exome sequencings in myopathies: findings from the French PFMG2025 initiative

Abstract Background Myopathies represent a very heterogeneous group of disease with multiple underlying causes, challenging for molecular genetic diagnosis. Hence, the diagnostic yield is very variable within the different myopathy subtypes. Current diagnostic strategies mainly rely on gene-panel or exome sequencing (ES) approaches, but they remain limited by the lack of analysis of deep intronic regions. In this study, we evaluated the diagnostic performance of a Genome Sequencing (GS) strategy for cases that were previously unresolved by gene-panel or ES in the context of myopathy diagnosis, as part of a large national scale GS strategy piloted by the French Genomic Medicine Initiative (PFMG2025). Methods Two hundred and sixty-five patients with genetically undiagnosed myopathy who underwent GS analysis as part of the PFMG2025 from July 2020 to October 2024 were included in this retrospective study. Clinical, paraclinical and genetics data were collected from the two clinical GS laboratories SeqOIA (Paris, France) and AURAGEN (Lyon, France). Results The diagnostic yield of GS in this study was of 26%, corresponding to a conclusive molecular diagnosis identifying likely pathogenic (ACMG class 4) or pathogenic (ACMG class 5) variants for 68/265 families. When considering candidate variants of unknown significance (VUS) that raised a strong diagnostic hypothesis, the diagnostic yield increased to 44%. GS was necessary for the resolution of 20.5% of cases with conclusive or candidate findings, as the variant should not have been detected using other techniques. Conclusions This nationwide program for the molecular diagnosis of myopathy showed GS as a valuable and feasible approach allowing the elucidation of complex variants and the discovery of new pathogenic mechanisms. These results highlight the complex nature of neuromuscular genetic disorders and show how GS can help providing a genetic diagnosis for these conditions in a clinical practice.

Authors

Institutions

Publication Details

Journal
Genome Medicine
Published
2026-09-17
DOI
https://doi.org/10.1186/s13073-026-01769-w
Primary Topic
Inflammatory Myopathies and Dermatomyositis
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
article

Genome sequencing improves diagnostic outcomes over panel and exome sequencings in myopathies: findings from the French PFMG2025 initiative

Béatrice Lannes, Julian Delanne, Manon Godin, Ivana Dabaj et al.
Genome Medicine
Inflammatory Myopathies and Dermatomyositis
article

Genome sequencing improves diagnostic outcomes over panel and exome sequencings in myopathies: findings from the French PFMG2025 initiative

Béatrice Lannes, Julian Delanne, Manon Godin, Ivana Dabaj, Jean‐Baptiste Chanson, Céline Poirsier, Marina Konyukh, Benjamin Dauriat, Klaus Dieterich, Marco Spinazzi, Pénélope Jordan, Alix de Becdelièvre, Sarah Souvannanorath, Julien Praline, Damien Sternberg, E. Malfatti, Sarah Louis Leonard, Mathilde Duchesne, Julien Fauré, Aurélien Juven, Anthony Maino, Isabelle Desguerre, Rita Menassa, Annabelle Chaussenot, Léa Declerck, Marlène Rio, Maud Michaud, Apolline Imbard, Antoine Pégat, Caroline Espil‐Taris, Thomas Courtin, Francis Ramond, Charlotte Dubucs, Beatrice Labella, Christine Barnérias, Frédérique Audic, Camille Verebi, Armelle Magot, Gaelle Gousse, Leïla Ghesh, Juliette Nectoux, Delphine Dupin‐Deguine, Mireille Cossée, Sandra Mercier, Jean-Baptiste Davion, Nicolas Gruchy, Laurent Magy, Anne‐Marie Guerrot, Pascal Cintas, Éric Bieth, Florence Esselin, Laurence Faivre, Véronique Manel, Marie‐Christine Nouguès, Ariane Choumert, Arnaud Isapof, Jean‐Baptiste Noury, Magalie Lodin, Raul Juntas-Morales, Corinne Metay, François-Jérôme Authier, Elisabeth Sarrazin, Claire Lefeuvre, Ariane Lunati, Marie-Line Jacquemont, Marilyn Lackmy, Martial Mallaret, Clément Guemy, Pascale Marcorelles, Pascal Laforet, Svetlana Gorokhova, Marion Masingue, Claude Cances, Guillaume Bassez, France Leturcq, Edouard Berling, Olivier Patat, Martin Krahn, Gorka Fernandez, Sabrina Sacconi, Florence Petit, Pauline Monin-Pre, Françoise Bouhour, Catherine Sarret, Emmanuelle Pion, Ana Ferreiro, Claude-Alain Maurage, Laurence Michel, Marie-Laure Martin-Negrier, Teresinha Evangelista, Elisabeth Ollagnon, François Constant Boyer, Anthony Behin, Yann Pereon, Aleksandra Nadaj-Pakleza, Juliette Ropars, Bertrand Isidor, Clément Hersent, Léonard Feasson, Elise Pisan
article en

Abstract

Abstract Background Myopathies represent a very heterogeneous group of disease with multiple underlying causes, challenging for molecular genetic diagnosis. Hence, the diagnostic yield is very variable within the different myopathy subtypes. Current diagnostic strategies mainly rely on gene-panel or exome sequencing (ES) approaches, but they remain limited by the lack of analysis of deep intronic regions. In this study, we evaluated the diagnostic performance of a Genome Sequencing (GS) strategy for cases that were previously unresolved by gene-panel or ES in the context of myopathy diagnosis, as part of a large national scale GS strategy piloted by the French Genomic Medicine Initiative (PFMG2025). Methods Two hundred and sixty-five patients with genetically undiagnosed myopathy who underwent GS analysis as part of the PFMG2025 from July 2020 to October 2024 were included in this retrospective study. Clinical, paraclinical and genetics data were collected from the two clinical GS laboratories SeqOIA (Paris, France) and AURAGEN (Lyon, France). Results The diagnostic yield of GS in this study was of 26%, corresponding to a conclusive molecular diagnosis identifying likely pathogenic (ACMG class 4) or pathogenic (ACMG class 5) variants for 68/265 families. When considering candidate variants of unknown significance (VUS) that raised a strong diagnostic hypothesis, the diagnostic yield increased to 44%. GS was necessary for the resolution of 20.5% of cases with conclusive or candidate findings, as the variant should not have been detected using other techniques. Conclusions This nationwide program for the molecular diagnosis of myopathy showed GS as a valuable and feasible approach allowing the elucidation of complex variants and the discovery of new pathogenic mechanisms. These results highlight the complex nature of neuromuscular genetic disorders and show how GS can help providing a genetic diagnosis for these conditions in a clinical practice.

Genome Medicine
Centre National de la Recherche Scientifique (FR), Université de Pau et des Pays de l'Adour (FR), Inserm (FR), Université Paris-Est Créteil (FR), Université de Montpellier (FR), Université Paris Cité (FR), Aix-Marseille Université (FR), Centre Hospitalier Universitaire de Grenoble (FR), Physiologie et Médecine Expérimentale du Coeur et des Muscles (FR), Hôpital Cochin (FR), Assistance Publique – Hôpitaux de Paris (FR), Hospices Civils de Lyon (FR), Institut de Myologie (FR), Institut de Génétique Moléculaire de Montpellier (FR), Stragen (France) (FR), Hôpitaux Universitaires Henri-Mondor (FR), Institut Universitaire de Recherche Clinique (FR), Grenoble Institute of Neurosciences (FR), Centre Hospitalier Universitaire de Saint-Étienne (FR), Institut Mondor de Recherche Biomédicale (FR), Hôpital de la Timone (FR), Centre de Génétique Médicale de Marseille (FR), Centre de Recherche en Myologie, Université Grenoble Alpes (FR)
Partnerships for the goals
Openalex Percentile: Top 10%
Inflammatory Myopathies and Dermatomyositis
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.