Using Exome Data to Identify Malignant Hyperthermia Susceptibility Mutations

Abstract

Background Malignant hyperthermia susceptibility (MHS) is a life-threatening, inherited disorder of muscle calcium metabolism, triggered by anesthetics and depolarizing muscle relaxants. An unselected cohort was screened for MHS mutations using exome sequencing. Our aim was to pilot a strategy for the RYR1 and CACNA1S genes. Methods Exome sequencing was performed on 870 volunteers not ascertained for MHS. Variants in RYR1 and CACNA1S were annotated using an algorithm that filtered results based on mutation type, frequency, and information in mutation databases. Variants were scored on a six-point pathogenicity scale. Medical histories and pedigrees were reviewed for malignant hyperthermia and related disorders. Results We identified 70 RYR1 and 53 CACNA1S variants among 870 exomes. Sixty-three RYR1 and 41 CACNA1S variants passed the quality and frequency metrics but we excluded synonymous variants. In RYR1, we identified 65 missense mutations, one nonsense, two that affected splicing, and one non frameshift indel. In CACNA1S, 48 missense, one frameshift deletion, one splicing and one non frameshift indel were identified. RYR1 variants predicted to be pathogenic for MHS were found in three participants without medical or family histories of MHS. Numerous variants, previously described as pathogenic in mutation databases, were reclassified by us to be of unknown pathogenicity. Conclusions Exome sequencing can identify asymptomatic patients at risk for MHS, although the interpretation of exome variants can be challenging. The use of exome sequencing in unselected cohorts is an important tool to understand the prevalence and penetrance of MHS, a critical challenge for the field.

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

“…Initial efforts using whole exome sequencing have largely resulted in validation of RYR1 mutations as the primary cause of disease in the majority of cases [11,16]. These studies have also revealed many RYR1 variants of unknown significance that require further validation in order to be listed as pathogenic.…”

“…It is now clear that RYR1-related myopathies are the most common nondystrophic muscle conditions of childhood and that the clinical spectrum for the disorders is vast [36,37]. One important issue to emerge is how to interpret identified sequence variants in RYR1 that are of uncertain pathogenicity [11,16]. AS RYR1 mutations are associated with such a broad range of disease, most novel variants identified in RYR1 have the potential of causing disease.…”

“…Mutations in two genes encoding triad proteins are well established as causes of MHS. The most common genetic change, occurring in>70% of individuals with genetically solved MH, is mutation in the skeletal muscle ryanodine receptor (RYR1) [6,11,12]. Mutations in RYR1 associated with MH are almost always heterozygous missense changes that alter protein function [13].…”

RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle ryanodine receptor dysfunction

“…In support of this point, exome sequencing performed on 870 volunteers without medical or family histories for MHS identified three RYR1 variants predicted to predispose to MH reactions. [39] Finally, the case reported by Potts et al illustrate the continuous use of dantrolene for treatment of cramps and prevention of RM: these 30-year-old identical twin brothers with persistent hyperCKemia, severe debilitating muscle cramps, and unexplained RM both required oral dantrolene therapy to control their symptoms [34].…”

Round Table on Malignant Hyperthermia in Physically Active Populations: Meeting Proceedings

“…24 The prevalence of genetic variants associated with MH susceptibility was estimated at 1 in 3000. 1,25 To date, 34 RYR1 variants and 2 CACNA1S variants have been confirmed as causing MH and recommended for diagnostic genetic testing by the European Malignant Hyperthermia Group. 14 4.…”