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

Author:

Mohan Shruthi1,McNulty Shannon1,Thaxton Courtney1,Elnagheeb Marwa1,Owens Emma1,Flowers May1,Nunnery Teagan1,Self Autumn1,Palus Brooke1,Gorokhova Svetlana23ORCID,Kennedy April4,Niu Zhiyv5ORCID,Johari Mridul67,Maiga Alassane Baneye8,Macalalad Kelly9,Clause Amanda R.9ORCID,Beckmann Jacques S.10,Bronicki Lucas11,Cooper Sandra T.121314,Ganesh Vijay S.1516,Kang Peter B.17ORCID,Kesari Akanchha18,Lek Monkol19,Levy Jennifer20,Rufibach Laura21,Savarese Marco7ORCID,Spencer Melissa J.22,Straub Volker23,Tasca Giorgio23ORCID,Weihl Conrad C.9

Affiliation:

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

Abstract

AbstractObjectiveLimb 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.MethodsThe 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.ResultsThe 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.InterpretationThe 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.

Funder

National Human Genome Research Institute

Publisher

Wiley

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