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.
Highlights
Malignant hyperthermia (MH) is a rare life-threatening pharmacogenetic disorder with the susceptibility inherited in an autosomal dominant pattern, but the disorder only happens upon exposure to a triggering agent
First, we present a case of MH in a 10-year-old boy harboring a family-specific variant in ryanodine receptor 1 (RYR1), p.(Cys2237Tyr), which is classified as likely pathogenic
When the clinical status of the proband was applied to the clinical grading scale to predict MH susceptibility, the proband received a score of 70 pts (15 pts each for masseter spasm, CK elevation, respiratory acidosis, inappropriate temperature increase, and 10 pts for acidosis), rendering the likelihood of an MH episode as almost certain [22]
Summary
Malignant hyperthermia (MH) is a rare life-threatening pharmacogenetic disorder with the susceptibility inherited in an autosomal dominant pattern, but the disorder only happens upon exposure to a triggering agent (volatile anesthetics and succinylcholine). We and others have sequenced whole genomes or whole exomes of a large set of individuals to perform genetic studies of common and rare diseases [7,8,9,10] These large-scale sequence datasets can be used as a reference of variant frequency in the context of clinical sequencing [11], but can lead to incidental findings. 1234567890();,: WGS set of 62 thousand Icelanders, followed by imputation into a total of 166 thousand Icelanders (chip-genotyped and/or wholegenome sequenced individuals), to determine the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S, according to current guidelines [12]. The proband had no overt signs of an overwhelming sepsis, he was afebrile and hemodynamically stable on
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