Open AccessGenetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients
Author(s) -
Nallamilli Babi Ramesh Reddy,
Chakravorty Samya,
Kesari Akanchha,
Tanner Alice,
Ankala Arunkanth,
Schneider Thomas,
da Silva Cristina,
Beadling Randall,
Alexander John J.,
Askree Syed Hussain,
Whitt Zachary,
Bean Lora,
Collins Christin,
Khadilkar Satish,
Gaitonde Pradnya,
Dastur Rashna,
Wicklund Matthew,
Mozaffar Tahseen,
Harms Matthew,
Rufibach Laura,
Mittal Plavi,
Hegde Madhuri
Publication year - 2018
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.649
Subject(s) - medicine , disease , genetic testing , population , compound heterozygosity , genetic heterogeneity , genetic diagnosis , genetics , bioinformatics , gene , phenotype , pathology , biology , environmental health
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.