Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database

Run Fridriksdottir, Arnar J. Jonsson, Brynjar O. Jensson, Kristinn O. Sverrisson, Gudny A. Arnadottir, Sigurbjorg J. Skarphedinsdottir, Hildigunnur Katrinardottir, Steinunn Snaebjornsdottir, Hakon Jonsson, Ogmundur Eiriksson, Gudjon R. Oskarsson, Asmundur Oddsson, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Gisli H. Sigurdsson, Einar P. Indridason, Stefan B. Sigurdsson, Gyda Bjornsdottir, Jona Saemundsdottir, Olafur T. MagnussonHans T. Bjornsson, Unnur Thorsteinsdottir, Theodor S. Sigurdsson, Patrick Sulem, Martin I. Sigurdsson, Kari Stefansson

Research output: Contribution to journalArticlepeer-review

Abstract

Malignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in RYR1 and CACNA1S. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in RYR1 and CACNA1S are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr) in the RYR1 gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband’s paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S. We observed 13 actionable variants in RYR1, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in CACNA1S. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.

Original languageEnglish (US)
JournalEuropean Journal of Human Genetics
DOIs
StateAccepted/In press - 2021

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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