Genetic landscape of Limb-Girdle Muscular Dystrophies from a Large Cohort of Neuromuscular Disease Patients (S42.002)

Objective: Our goal was to understand the percent-contribution of genes or the genetic-landscape of LGMDs. Background: Limb-girdle muscular dystrophies (LGMD) are a group of heterogeneous genetic disorders predominantly involved in proximal muscle-weakness with an autosomal-recessive or -dominant inheritance. To date, >30 genes are known to be associated with different LGMD subtypes. The clinical-genetic heterogeneities in LGMD make disease diagnosis complicated and expensive. Design/Methods: Recently, MDA/Jain-Foundation jointly launched a LGMD sequencing program with the 35 gene NGS-panel, through which >3000 patients were sequenced. Results: 40% of the patients had a definitive molecular diagnosis with majority having mutations in either of 5 genes: CAPN3 , DYSF , ANO5 , FKRP , COL6A1 , suggesting them as the major contributors to LGMD. Interestingly, late-onset Pompe, a rare, but treatable lysosomal-storage disorder of glycogen-accumulation, muscle-weakness, often shows LGMD-like phenotype. We successfully identified >21 late-onset Pompe patients with pathogenic variants in GAA gene. We also identified multiple patients with two TTN pathogenic variants suggestive of functional study requirements to understand Titin pathophysiological role in recessive muscle disorders. More interestingly, in at least 10% of the patients, pathogenic variants were detected in more than one LGMD gene. For example, one patient clinically diagnosed with LGMD2L but showing abnormal progression had homozygous pathogenic variants in both ANO5 and SGCA genes. Similar multigenic combinations of pathogenic variants were detected in many other individuals suggesting a possible role of “synergistic heterozygosity” and/or “digenic contribution” to disease presentation and progression. Also ~25% of patients have been identified with variants of unknown significance (VOUS) which clearly suggests the need for functional-analysis for pathogenicity-testing, facilitating enrolment in numerous available clinical trials. Increased diagnostic-yield was observed in LGMD gene-panel testing compared to exome sequencing. Conclusions: Overall, this large-scale LGMD sequencing project has tremendously improved understanding of the different LGMD subtypes’ relative prevalence, allowing timely management and participation of affected individuals in clinical trials. Disclosure: Dr. Chakravorty has nothing to disclose. Dr. Ramesh has nothing to disclose. Dr. Cheng has nothing to disclose. Dr. Wicklund has received personal compensation for activities with Genzyme. Dr. Wicklund has received research support from Sarepta, Genzyme, and Marathon. Dr. Harms has received personal compensation for activities with Sanofi-Genzyme and Sun Pharmaceuticals as a speaker. Dr. Harms has received personal compensation for activities as an expert witness testimony. Dr. Harms has received personal compensation for activities with Sanofi-Genzyme as a scientific advisory board member. Dr. Harms has received research support from Biogen Idec. Dr. Mozaffar has received personal compensation for activities with Sanofi Genzyme, Grifols, Amicus, Biomarin, Idera Pharmaceuticals and Ultragenyx. Dr. Mozaffar has received research support from Cytokinetics, Alexion, Amicus, Biomarin, Grifols, GlaxoSmithKline, Ultragenyx, and Novartis. Dr. Hegde has nothing to disclose.