Investigating candidate modifier loci in malignant hyperthermia susceptibility using CRISPR/Cas gene editing

Previous studies indicate more than one gene may be involved in determining susceptibility to malignant hyperthermia (MH) in individuals.1 2 Thus a threshold model of MH, whereby several genes may contribute to phenotype through both major and modifier effects, may be more suitable than a classical single gene disorder model. We have previously found that variants in both PYGM and CPT2 are over-represented amongst individuals susceptible to MH. We aimed to examine whether loss of function in these genes has a modifying effect on caffeine-induced calcium release in mouse skeletal muscle cells modelling the RYR1 variant most commonly associated with MH in the UK.