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.

恶性高热 (MH) 易感性是一种罕见的危及生命的疾病，会在接触触发剂时发生。MH 通常是由于RYR1和CACNA1S中的蛋白质改变变体。美国医学遗传学和基因组学学院建议，当偶然发现RYR1和CACNA1S的致病性和可能致病性变异时，应向携带者报告。可操作变体的检测允许避免在麻醉期间暴露于触发剂。首先，我们报告了一名 10 岁冰岛先证者疑似 MH 事件，在 RYR1 中含有杂合错义变异 NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr )可能致病的基因。该变体对一个三代家族中的四个人是私有的，并且在 62,240 名全基因组测序 (WGS) 冰岛人中不存在。单倍型共享和 WGS 显示该变体以体细胞嵌合体的形式出现，也存在于先证者的祖母的种系中。其次，我们使用一组 62,240 名具有 WGS 的冰岛人，评估了RYR1和CACNA1S中可操作的致病性和可能的​​致病性变异的携带频率。我们在RYR1中观察到 13 个可操作变体，基于 ClinVar 分类，由 43 名冰岛人携带，在CACNA1S中没有可操作变体. 1450 名冰岛人中就有一人携带 MH 的可操作变体。广泛的测序允许对变异进行更好的分类和精确的约会，并且大部分人群的 WGS 导致偶然发现可操作的 MH 基因型。