Expert classification of the clinical significance of DYSF variants for limb girdle muscular dystrophy

Topic:

Clinical Management

Poster Number: 327 T

Author(s):

Laura Rufibach, PhD, Jain Foundation, Amanda Clause, PhD, Washington University in St. Louis, Alka Malhotra, PhD, Washington University In Saint Louis, William Lowery, MD, LGMD-1D DNAJB6 Foundation, Natasha Persaud, MS, The Hospital for Sick Children, Jacques Beckmann, MD, PhD, University of Lausanne, Adam Bournazos, PhD, Children's Medical Research Institute, Samantha Bryen, PhD, Garvan Institute of Medical Research, Sandra Cooper, PhD, The University of Sydney, Vijay Ganesh, MD, PhD, Brigham and Women's Hospital, Alison Gaynor, PhD, Virginia Commonwealth University, Svetlana Gorokhova, MD, PhD, NIH/NINDS/NNDCS, Jessica Hornick, PhD, Myriad Women's Health, Haojun Margaret Huang, PhD, BC Cancer Agency, Mridul Johari, PhD, University of Western Australia, Australia., Peter Kang, MD, University of Minnesota, Akanchha Kesari, PhD, FACMG, Illumina Inc., Jennifer Levy, PhD, Coalition to Cure Calpain 3, Leonela Luce, PhD, John Walton Muscular Dystrophy Research Centre, Jaimie Miser, PhD, Natera, Babi Ramesh Reddy Nallamilli, PhD, FACMG, Revvity Omics, Emma Owens, University of North Carolina at Chapel Hill, Marco Savarese, PhD, Folkhälsan Research Center, Volker Straub, MD, PhD, John Walton Muscular Dystrophy Research Centre, Giorgio Tasca, MD, PhD, John Walton Muscular Dystrophy Research Centre, Ana Topf, PhD, John Walton Muscular Dystrophy Research Centre, James Wang, PhD, LabCorp, Conrad Weihl, MD, PhD, Washington University St Louis, Monkol Lek, PhD, Yale University

Limb girdle muscular dystrophy (LGMD) is a genetically heterogeneous disorder of progressive muscle weakness caused by variants in >30 genes. Accurate genetic diagnosis aids clinical management and is necessary for access to clinical studies and trials, yet up to half of patients undergoing genetic testing do not receive a definitive diagnosis, with many having variants of uncertain significance (VUS). Variants in the DYSF gene are one of the most common causes of LGMD, with a large number of VUS. To improve the genetic diagnosis of LGMD and reduce VUS, we formed a ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel and developed FDA-recognized variant classification guidelines tailored to DYSF.

Our DYSF-specific guidelines build on years of research elucidating the underlying mechanisms of disease. We clinically validated a functional assay of dysferlin membrane localization and showed that loss of dysferlin protein expression in patient skeletal muscle or blood monocytes provides strong evidence of variant pathogenicity. To date, loss of dysferlin protein expression in patient tissue as an indicator of pathogenicity was used in 85% of variants we classified as Likely Pathogenic or Pathogenic, emphasizing the impact of this feature of patient phenotype for confirming genetic diagnosis.

To further demonstrate the utility of our guidelines, we are applying them to DYSF variants with uncertain or conflicting assertions of pathogenicity. We currently have a 42% success rate in resolving the classification of variants considered VUS in the public ClinVar database, and an 89% success rate in resolving the classification of variants with conflicting assertions. In collaboration with the Jain Foundation, we also curated variants classified as VUS in participants in the Dysferlin Registry and were able to resolve the classification of 81%, providing valuable clarification on the genetic diagnosis of these individuals. Our work on DYSF shows that gene-specific variant classification guidelines can resolve uncertainty around variant pathogenicity and improve genetic diagnosis of LGMD.