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Author Notes:

Correspondence: Madhuri Hegde, Emory University School of Medicine, Department of Human Genetics, Whitehead Building Suite 301, 615 Michael Street NE, Atlanta, GA 30322. Tel: +1 470 337 2847/+1 404 727 1197; Fax: +1 404 727 3949; E-mail: mhegde@emory.edu

MH had full access to all of the data in the study and had responsibility for the integrity and accuracy of the data and its analysis.

MH, SC, BRRN, LR, PM, MW, and MH designed the study concept.

All authors contributed to the acquisition, analysis, or interpretation of data.

BRRN, SC, and MH drafted the manuscript.

All authors contributed to the critical revision of the manuscript for important scientific or intellectual content.

BRRN and SC performed statistical analysis.

MH obtained funding for this study.

MH provided administrative support and supervised the overall study.

The corresponding author MH had final responsibility for the decision to submit for publication.

We are greatly indebted to all the study participants and their families without them this research would not have been possible.

Conflict of Interest: Nothing to report.


Research Funding:

This work was jointly funded by the Muscular Dystrophy Association, and the Jain Foundation.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences
  • Neurosciences & Neurology

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

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Journal Title:

Annals of Clinical and Translational Neurology


Volume 5, Number 12


, Pages 1574-1587

Type of Work:

Article | Final Publisher PDF


Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. Objective: Limb-girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal-muscle weakness with >30 genes associated with different subtypes. The clinical-genetic overlap among subtypes and with other NMDs 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: CAPN3(17%), DYSF(16%), FKRP(9%) and ANO5(7%). We observed an increased prevalence of genetically confirmed late-onset Pompe disease, DNAJB6-associated LGMD subtype1E and CAPN3-associated autosomal-dominant LGMDs. 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.

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© 2018 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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