Identification of causative gene for Malignant Hyperthemia using exome sequencing

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We performed exome sequencing of Japanese families with malignant hyperthermia. All exons of RYR1 of the carrier in this family were directly sequenced in previous research and no causative mutation has been found. To detect disease causing mutation efficiently, we prepared sets of candidate genes that contain 1) genes related to calcium signaling, 2) genes located on malignant hyperthermia susceptibility loci, 3) genes expressed in tissues where RYR1 and CACNA1S are highly expressed or 4) genes that interact with CACNA1S or RYR1 directly or indirectly. Using data from exome sequencing and the candidate gene sets, we identified 5 plausible mutations. One of the mutations was in CACNA1S that codes voltage-gated L-type calcium channel alpha subunit. This subunit interacts with Ryanodine receptor 1. The functional validation if this mutation is really causative of this family awaits further study such as an electrophysiological experiment.