Frequency and localization of mutations in the 106 exons of theRYR1 gene in 50 individuals with malignant hyperthermia

Abstract

Communicated by Maria Rita Passos-BuenoMalignant hyperthermia (MH) is a dominantly inherited pharmacogenetic condition that manifests as a life-threatening hypermetabolic reaction when a susceptible individual is exposed to common volatile anesthetics and depolarizing muscle relaxants. Although MH appears to be genetically heterogeneous, RYR1 is the main candidate for MH susceptibility. However, since molecular analysis is generally limited to exons where mutations are more frequently detected, these are routinely found only in 30-50% of susceptible subjects. In this study the entire RYR1 coding region was analyzed in a cohort of 50 Italian MH susceptible (MHS) subjects. Thirty-one mutations, 16 of which were novel, were found in 43 individuals with a mutation detection rate of 86%, the highest reported for RYR1 in MH so far. These data provide clear evidence that mutations in the RYR1 gene are the predominant cause of MH.

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

“…13 The high RYR1 mutation detection rate observed in this study can be explained by the stringent selection criteria for enrolment into the study and by the mutation screening strategy, which consisted of sequence analysis of complete RYR1 transcripts. Comparable detection rates (70% to 86%) have been reported recently for other MHS populations [8][9][10] where genetic screening included the entire coding sequence of the gene. On the other hand, if only established MH causative mutations from the EMHG database (www.emhg.org) were considered, then the mutation detection rates or the diagnostic sensitivity of the genetic testing would be 42% in this study and from 28% to 33% in other studies.…”

“…On the other hand, if only established MH causative mutations from the EMHG database (www.emhg.org) were considered, then the mutation detection rates or the diagnostic sensitivity of the genetic testing would be 42% in this study and from 28% to 33% in other studies. [8][9][10] This does not compare favourably with a reported sensitivity of 97% to 99% for CHCT and in vitro contracture test (IVCT), respectively. 36,37 Published data indicate that the frequency of MH-causative RyR1 mutations is population-specific, with only a few mutations accounting for the majority of MH cases in some populations.…”

“…7 Malignant hyperthermia genetic research has shown that RYR1 is the major causal gene for MH as well as for a congenital myopathy, central core disease (CCD). 3,6 Malignant hyperthermia-associated RYR1 mutations have been found in 60% to 86% of MH families with diverse ethnicity, [8][9][10][11] and their distribution and frequency have been shown to be population-specific. 6 Recent improvements in molecular genetics methods have facilitated genetic analysis of the entire coding region of RYR1, which is *159,000 nucleotides long and contains 106 exons that are spliced into a 15 kb RYR1 mRNA transcript.…”

The Genetics of Malignant Hyperthermia

“…In other populations [4], the yield of positive results, if genetic testing were the initial test in a family, would be even lower. Seven patients referred for RYR1 exam due to elevated creatine kinase in the absence of personal or family experience of an acute MH event or positive muscle contracture test did not have RYR1 mutations [14]. These results support the need to evaluate detailed personal and family history when referring a patient for genetic testing of MHS.…”

“…In 50 Italian MHS individuals, the RYR1 mutation detection rate was 86% [14]. Sequence variants that may be causative of MH have been observed outside the hot spots.…”