Some people show an increased propensity to develop heat illness, rhabdomyolysis (muscle tissue breakdown) or both following heavy exercise suggesting a genetic contribution. Variants in a number of genes, including RYR1 are associated with rhabdomyolysis but the situation with exertional heat illness is less certain. We found potentially pathogenic (disease-related) variants in 20 genes in 38 of 64 patients (mostly military personnel) who had experienced exertional heat illness. We confirm a role of RYR1 in exertional heat illness and our data suggest that combinations of rare variants in genes involved in muscle calcium handling, muscle metabolism and muscle membrane regulation are implicated. (By Professor PM Hopkins, https://jmg.bmj.com/content/early/2020/02/13/jmedgenet-2019-106461 )