Investigating the genetic susceptibility to exertional heat illness.

Abstract

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. 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. We found 51 non-polymorphic, potentially pathogenic variants in 20 genes in 38 patients. Our data indicate that <i>RYR1</i> p.T3711M (previously shown to be likely pathogenic for MH susceptibility) and <i>RYR1</i> p.I3253T are likely pathogenic for EHI. <i>PYGM</i> 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 <i>CACNA1S</i> p.R498 has been found. Combinations of rare variants in the same or different genes are implicated in EHI. We confirm a role of <i>RYR1</i> 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.