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

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


Title: Sequence variants in malignant hyperthermia genes in Iceland : classification and actionable findings in a population database
Author: Fridriksdottir, Run
Jónsson, Arnar Jan
Jensson, Brynjar O.
Sverrisson, Kristinn O.
Arnadottir, Gudny A.
Skarphéðinsdóttir, Sigurbjorg J.
Katrinardottir, Hildigunnur
Snaebjornsdottir, Steinunn
Jonsson, Hakon
Eiriksson, Ogmundur
... 16 more authors Show all authors
Date: 2021-08-31
Language: English
Scope: 6
University/Institute: Landspitali - The National University Hospital of Iceland
University of Akureyri
Department: Perioperative Services
Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Series: European Journal of Human Genetics; 29(12)
ISSN: 1018-4813
DOI: https://doi.org/10.1038/s41431-021-00954-2
Subject: Genetics; Genetics (clinical)
URI: https://hdl.handle.net/20.500.11815/3109

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Citation:

Fridriksdottir , R , Jónsson , A J , Jensson , B O , Sverrisson , K O , Arnadottir , G A , Skarphéðinsdóttir , S J , Katrinardottir , H , Snaebjornsdottir , S , Jonsson , H , Eiriksson , O , Óskarsson , G R , Oddsson , A , Jonasdottir , A , Jonasdottir , A , Sigurdsson , G H , Indridason , E P , Sigurðsson , S B , Bjornsdottir , G , Saemundsdottir , J , Magnusson , O T , Björnsson , H T , Thorsteinsdottir , U , Sigurdsson , T S , Sulem , P , Sigurðsson , M I & Stefansson , K 2021 , ' Sequence variants in malignant hyperthermia genes in Iceland : classification and actionable findings in a population database ' , European Journal of Human Genetics , vol. 29 , no. 12 , pp. 1819-1824 . https://doi.org/10.1038/s41431-021-00954-2

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.

Description:

Funding Information: The study was funded by deCODE Genetics/Amgen Inc. Publisher Copyright: © 2021, The Author(s).

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