. 2024 Sep;11(9):2268-2276.

doi: 10.1002/acn3.52127. Epub 2024 Aug 30.

Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy

Shruthi Mohan¹, Shannon McNulty¹, Courtney Thaxton¹, Marwa Elnagheeb¹, Emma Owens¹, May Flowers¹, Teagan Nunnery¹, Autumn Self¹, Brooke Palus¹, Svetlana Gorokhova^{2

3}, April Kennedy⁴, Zhiyv Niu⁵, Mridul Johari^{6

7}, Alassane Baneye Maiga⁸, Kelly Macalalad⁹, Amanda R Clause⁹, Jacques S Beckmann¹⁰, Lucas Bronicki¹¹, Sandra T Cooper^{12

13

14}, Vijay S Ganesh^{15

16}, Peter B Kang¹⁷, Akanchha Kesari¹⁸, Monkol Lek¹⁹, Jennifer Levy²⁰, Laura Rufibach²¹, Marco Savarese⁷, Melissa J Spencer²², Volker Straub²³, Giorgio Tasca²³, Conrad C Weihl⁹

Affiliations

¹ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
² Aix Marseille Univ, INSERM, MMG, U 1251, Marseille, France.
³ Department of Medical Genetics, Timone Children's Hospital, APHM, Marseille, France.
⁴ Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
⁶ Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.
⁷ Folkhälsan Research Center, Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
⁸ Department of Medicine, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
⁹ Department of Neurology, Washington University School of Medicine in St. Louis, St Louis, Missouri, USA.
¹⁰ Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
¹¹ Department of clinical genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
¹² Kids Neuroscience Centre, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹³ School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Westmead, New South Wales, Australia.
¹⁴ Functional Neuromics, Children's Medical Research Institute, Westmead, New South Wales, Australia.
¹⁵ Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹⁶ Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁷ Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁸ Illumina Inc, San Diego, California, USA.
¹⁹ Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
²⁰ Coalition to Cure Calpain 3, Westport, Connecticut, USA.
²¹ Jain Foundation, Seattle, Washington, USA.
²² Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²³ John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle Upon Tyne, UK.

PMID: 39215466
PMCID: PMC11537137
DOI: 10.1002/acn3.52127

Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy

Shruthi Mohan et al. Ann Clin Transl Neurol. 2024 Sep.

. 2024 Sep;11(9):2268-2276.

doi: 10.1002/acn3.52127. Epub 2024 Aug 30.

Authors

Affiliations

¹ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
² Aix Marseille Univ, INSERM, MMG, U 1251, Marseille, France.
³ Department of Medical Genetics, Timone Children's Hospital, APHM, Marseille, France.
⁴ Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
⁶ Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.
⁷ Folkhälsan Research Center, Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
⁸ Department of Medicine, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
⁹ Department of Neurology, Washington University School of Medicine in St. Louis, St Louis, Missouri, USA.
¹⁰ Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
¹¹ Department of clinical genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
¹² Kids Neuroscience Centre, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹³ School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Westmead, New South Wales, Australia.
¹⁴ Functional Neuromics, Children's Medical Research Institute, Westmead, New South Wales, Australia.
¹⁵ Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹⁶ Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁷ Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁸ Illumina Inc, San Diego, California, USA.
¹⁹ Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
²⁰ Coalition to Cure Calpain 3, Westport, Connecticut, USA.
²¹ Jain Foundation, Seattle, Washington, USA.
²² Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²³ John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle Upon Tyne, UK.

PMID: 39215466
PMCID: PMC11537137
DOI: 10.1002/acn3.52127

Abstract

Objective: Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD.

Methods: The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD.

Results: The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD.

Interpretation: The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Figure 1**
Curation classifications of the 35 gene–disease relationships curated by the MDM GCEP. Genetic and experimental evidence scores of the 35 gene–disease relationships. *POMGNT1* and *DAG1*, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD and are noted in red. *denote genes co‐curated by the congenital myopathy and MDM GCEP.

**Figure 2**
Mondo revision recommended by the MDM GCEP for the muscular dystrophy‐dystroglycanopathy genes. (A) Previous parent (+) and child (−) terms for α‐dystroglycanopathy genes. (B) Proposed parent and child terms for α‐dystroglycanopathy genes.

See this image and copyright information in PMC

Update of

Expert Panel Curation of 31 Genes in Relation to Limb Girdle Muscular Dystrophy.
Mohan S, McNulty S, Thaxton C, Elnagheeb M, Owens E, Flowers M, Nunnery T, Self A, Palus B, Gorokhova S, Kennedy A, Niu Z, Johari M, Maiga AB, Macalalad K, Clause AR, Beckmann JS, Bronicki L, Cooper ST, Ganesh VS, Kang PB, Kesari A, Lek M, Levy J, Rufibach L, Savarese M, Spencer MJ, Straub V, Tasca G, Weihl CC. Mohan S, et al. bioRxiv [Preprint]. 2024 May 6:2024.05.03.592369. doi: 10.1101/2024.05.03.592369. bioRxiv. 2024. Update in: Ann Clin Transl Neurol. 2024 Sep;11(9):2268-2276. doi: 10.1002/acn3.52127. PMID: 38765987 Free PMC article. Updated. Preprint.

References

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1. Strafella C, Campoli G, Galota RM, et al. Limb‐girdle muscular dystrophies (LGMDs): the clinical application of NGS analysis, a family case report. Front Neurol. 2019;10:619. - PMC - PubMed
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Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy

Affiliations

Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous