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Objective  Limb‐girdle muscular dystrophies ( LGMD s), one of the most heterogeneous neuromuscular disorders ( NMD s), involves predominantly proximal‐muscle weakness with >30 genes associated with different subtypes. The clinical‐genetic overlap among subtypes and with other  NMD s complicate disease‐subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical‐trial recruitment. Currently seven  LGMD  clinical trials are active but still no gene‐therapy‐related treatment is available. Till‐date no nation‐wide large‐scale  LGMD  sequencing program was performed. Our objectives were to understand  LGMD  genetic basis, different subtypes’ relative prevalence across  US  and investigate underlying disease mechanisms.    Methods  A total of 4656 patients with clinically suspected‐ LGMD  across  US  were recruited to conduct next‐generation sequencing ( NGS )‐based gene‐panel testing during June‐2015 to June‐2017 in  CLIA ‐ CAP ‐certified Emory‐Genetics‐Laboratory. Thirty‐five  LGMD ‐subtypes‐associated or  LGMD ‐like other  NMD ‐associated genes were investigated. Main outcomes were diagnostic yield, gene‐variant spectrum, and  LGMD  subtypes’ prevalence in a large  US LGMD ‐suspected population.    Results  Molecular diagnosis was established in 27% (1259 cases; 95%  CI , 26–29%) of the patients with major contributing genes to  LGMD  phenotypes being:   CAPN 3 (17%),   DYSF  (16%),   FKRP  (9%) and   ANO 5 (7%). We observed an increased prevalence of genetically confirmed late‐onset Pompe disease,   DNAJB 6‐ associated  LGMD  subtype1E and   CAPN 3 ‐associated autosomal‐dominant  LGMD s. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one  LGMD  gene suggesting possible synergistic heterozygosity/digenic/multigenic contribution to disease presentation/progression that needs consideration as a part of diagnostic modality.    Interpretation  Overall, this study has improved our understanding of the relative prevalence of different  LGMD  subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients