A multi-dimensional analysis of genotype-phenotype discordance in malignant hyperthermia susceptibility.
A multi-dimensional analysis of genotype-phenotype discordance in malignant hyperthermia susceptibility.
复制标题
恶性高热易感性基因型-表型不一致的多维分析。
DOI：
10.1016/j.bja.2020.07.042
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发表时间：
2020
影响因子：
9.8
通讯作者：
Riazi,Sheila
中科院分区：
文献类型：
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作者：
IbarraMoreno,CarlosA;Kraeva,Natalia;Zvaritch,Elena;Figueroa,Lourdes;Rios,Eduardo;Biesecker,Leslie;VanPetegem,Filip;Hopkins,PhilipM;Riazi,Sheila
背景恶性高热 (MH) 易感性是一种遗传性疾病，可通过致病性遗传变异的存在或通过玻璃咖啡因-氟烷挛缩测试来诊断。通过多维方法，我们描述了一名有可能 MH 家族史的患者的遗传和体外测试结果之间不一致的影响。方法该患者的兄弟有可能的 MH 反应，根据北美 MH 组方案进行了咖啡因-氟烷挛缩试验 (CHCT)。使用桑格测序完成了完整 RYR1 和 CACNA1 转录本的筛选。其他功能分析包括皮肤肌纤维钙诱导的钙释放敏感性、培养肌管中的钙信号传导测定，以及任何遗传变异对其化学环境的影响的计算机评估。结果患者的 CHCT 结果呈阴性，但她携带 RYR1 变异 c.1209C>G，p.Ile403Met，该变异被欧洲恶性高热组列为致病性。功能测试表明具有微弱影响的功能获得效应，预计该变体会影响 RyR1 蛋白 3D 结构的折叠稳定性。根据美国医学遗传学和基因组学学院/分子病理学协会指南，该变异将被定性为意义不确定的变异。 结论 现有数据并未证实或排除该患者 MH 风险增加。需要进一步研究将 RyR1 功能测定（包括当前 MH 易感性的金标准测试）与临床表型关联起来。应重新评估与 MH 易感性相关的遗传变异的致病性。
BackgroundMalignant hyperthermia (MH) susceptibility is an inherited condition, diagnosed either by the presence of a pathogenic genetic variant or byin vitrocaffeine–halothane contracture testing. Through a multi-dimensional approach, we describe the implications of discordance between genetic andin vitrotest results in a patient with a family history of possible MH.MethodsThe patient, whose brother had a possible MH reaction, underwent the caffeine–halothane contracture test (CHCT) according to the North American MH Group protocol. Screening of the completeRYR1andCACNA1Stranscripts was done using Sanger sequencing. Additional functional analyses included skinned myofibre calcium-induced calcium release sensitivity, calcium signalling assays in cultured myotubes, andin silicoevaluation of the effect of any genetic variants on their chemical environment.ResultsThe patient's CHCT result was negative but she carried anRYR1variant c.1209C>G, p.Ile403Met, that is listed as pathogenic by the European Malignant Hyperthermia Group. Functional tests indicated a gain-of-function effect with a weak impact, and the variant was predicted to affect the folding stability of the 3D structure of the RyR1 protein. Based on American College of Medical Genetics and Genomics/Association of Molecular Pathology guidelines, this variant would be characterised as a variant of uncertain significance.ConclusionsAvailable data do not confirm or exclude an increased risk of MH for this patient. Further research is needed to correlate RyR1 functional assays, including the current gold standard testing for MH susceptibility, with clinical phenotypes. The pathogenicity of genetic variants associated with MH susceptibility should be re-evaluated.