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Ann Clin Transl Neurol. 2018 Dec 1;5(12):1574-1587. doi: 10.1002/acn3.649. eCollection 2018 Dec.

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

Author information

1
Emory University Department of Human Genetics Atlanta Georgia 30322.
2
EGL Genetics-Eurofins Tucker Atlanta Georgia 30084.
3
Augusta University Augusta Georgia 30912.
4
Department of Neurology Bombay Hospital Mumbai Maharashtra India.
5
Department of Neurology Sir J J Group of Hospitals Grant Medical College Mumbai Maharashtra India.
6
Centre for Advanced Molecular Diagnostics in Neuromuscular Disorders (CAMDND) 400022 Mumbai India.
7
Neurology The University of Colorado at Denver - Anschutz Medical Campus Aurora Colorado 80045.
8
Neurology University of California, Irvine Orange California 92868.
9
Department of Neurology Columbia University New York New York 10032.
10
Jain Foundation Seattle Wisconsin 98115.
11
In-Depth Genomics Bellevue Washington.

Abstract

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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