Background We aimed to identify rare (minor allele frequency ≤1%), potentially pathogenic non-synonymous variants in a well-characterised cohort with a clinical history of exertional heat illness (EHI) or exertional rhabdomyolysis (ER). The genetic link between malignant hyperthermia (MH) and EHI was investigated due to their phenotypic overlap.
Methods The coding regions of 38 genes relating to skeletal muscle calcium homeostasis or exercise intolerance were sequenced in 64 patients (mostly military personnel) with a history of EHI, or ER and who were phenotyped using skeletal muscle in vitro contracture tests. We assessed the pathogenicity of variants using prevalence data, in silico analysis, phenotype and segregation evidence and by review of the literature.
Results We found 51 non-polymorphic, potentially pathogenic variants in 20 genes in 38 patients. Our data indicate that RYR1 p.T3711M (previously shown to be likely pathogenic for MH susceptibility) and RYR1 p.I3253T are likely pathogenic for EHI. PYGM p.A193S was found in 3 patients with EHI, which is significantly greater than the control prevalence (p=0.000025). We report the second case of EHI in which a missense variant at CACNA1S p.R498 has been found. Combinations of rare variants in the same or different genes are implicated in EHI.
Conclusion We confirm a role of RYR1 in the heritability of EHI as well as ER but highlight the likely genetic heterogeneity of these complex conditions. We propose defects, or combinations of defects, in skeletal muscle calcium homeostasis, oxidative metabolism and membrane excitability are associated with EHI.
- exertion heat illness
- skeletal muscle
- calcium signalling
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Contributors Conception and design of the study: PH, M-AS. Conduct of experiments and data collection: LG, DM, PG, CD, CH, DRdS, PH. Data analysis and interpretation: all authors. Drafting of manuscript: LG. All authors reviewed drafts of the manuscript and approved the final version.
Funding National Institutes of Health (NIH): National Institute of Arthritis, Musculoskeletal and Skin Diseases (2P01 AR-05235; PM-H). The Colt Foundation (Charity registered No. 277189, PhD studentship awarded to LG, supervisors PMH and M-AS).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Research ethics approval was granted by Leeds (East) Research Ethics Committee or its predecessors (10/H1306/70) and patients provided written consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.