Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel

Justyne E Ross¹, May Flowers¹, Shannon McNulty¹, Mayher Patel², Hui Yang³, Brooke Palus¹, Marwa Abdelmoneim Elnagheeb¹, Lucy Eng¹, Emma Owens¹, Alan H Beggs⁴, Enrico Bertini⁵, Adele D'Amico⁵, Sandra Donkervoort⁶, James Dowling⁷, Fabiana Fattori⁵, Ana Ferreiro⁸, Casie A Genetti⁴, Hernan Gonorazky⁸, Monkol Lek⁹, Amanda Lindy³, Livija Medne¹⁰, Francesco Muntoni¹¹, Sander Pajusalu^{9

12

13}, Katarina Pelin¹⁴, John Rendu¹⁵, Anna Sarkozy¹¹, Matteo Vatta¹⁶, Tom Winder¹⁶, Grace Yoon¹⁷, Carsten G Bönnemann⁶, Ozge Ceyhan-Birsoy¹⁸

Affiliations

¹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ GeneDx, Gaithersburg, MD, USA.
⁴ Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁵ Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁶ Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, National Institute of Neurological Disorders, Bethesda, USA.
⁷ Division of Neurology, Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada.
⁸ Basic and Translational Myology Laboratory, Université de Paris, Paris, France.
⁹ Department of Genetics, Yale School of Medicine, New Haven, USA.
¹⁰ Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, USA.
¹¹ Dubowitz Neuromuscular Centre, University College London Great Ormond Street Institute of Child Health, London, UK.
¹² Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
¹³ Genetic and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
¹⁴ Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
¹⁵ Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France.
¹⁶ Labcorp Genetics Inc. (formerly Invitae Corp.), San Francisco, CA, USA.
¹⁷ Divisions of Neurology and Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada.
¹⁸ Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

PMID: 40491337
DOI: 10.1177/22143602251339369

Free article

Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel

Justyne E Ross et al. J Neuromuscul Dis. 2025.

Free article

. 2025 Jun 10:22143602251339369.

doi: 10.1177/22143602251339369. Online ahead of print.

Authors

Affiliations

¹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ GeneDx, Gaithersburg, MD, USA.
⁴ Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁵ Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁶ Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, National Institute of Neurological Disorders, Bethesda, USA.
⁷ Division of Neurology, Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada.
⁸ Basic and Translational Myology Laboratory, Université de Paris, Paris, France.
⁹ Department of Genetics, Yale School of Medicine, New Haven, USA.
¹⁰ Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, USA.
¹¹ Dubowitz Neuromuscular Centre, University College London Great Ormond Street Institute of Child Health, London, UK.
¹² Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
¹³ Genetic and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
¹⁴ Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
¹⁵ Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France.
¹⁶ Labcorp Genetics Inc. (formerly Invitae Corp.), San Francisco, CA, USA.
¹⁷ Divisions of Neurology and Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada.
¹⁸ Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

PMID: 40491337
DOI: 10.1177/22143602251339369

Abstract

Background: Congenital myopathies are a group of neuromuscular disorders that typically present at birth or early childhood with hypotonia and non-progressive or slowly progressive muscle weakness. They are classically subclassified by characteristic structural changes and histopathological findings in skeletal muscle. Variants in over 40 genes have been described to date in patients with various forms of congenital myopathy with overlapping phenotypic and histological features, which poses a challenge for laboratories and clinicians in interpreting genetic findings.

Objective: The purpose of this study was to evaluate the evidence supporting each gene-disease relationship and provide an expert-reviewed classification for the clinical validity of genes involved in congenital myopathies.

Methods: The ClinGen Neurological Disorders Clinical Domain Working Group assembled the Congenital Myopathies Gene Curation Expert Panel (CongenMyopathy-GCEP), a group of clinicians and geneticists with expertise in congenital myopathies tasked to perform evidence-based curation of 50 gene-disease relationships using the ClinGen semiquantitative framework to assign clinical validity.

Results: Our curation effort resulted in 35 (70%) Definitive, eight (16%) Moderate, six (12%) Limited, and one (2%) Disputed disease relationship classifications. The summary of each curation is made publicly available on the ClinGen website.

Conclusions: Expert-reviewed assignment of gene-disease relationships by the CongenMyopathy-GCEP facilitates accurate molecular diagnoses for congenital myopathies and can allow genetic testing to focus on genes with a validated role in disease.

Keywords: Genetics; congenital myopathy; genetic testing; neuromuscular disease.

PubMed Disclaimer

LinkOut - more resources

Full Text Sources
- Atypon
- IOS Press

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel

Affiliations

Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel

Authors

Affiliations

Abstract

LinkOut - more resources

Full Text Sources