Roberts David A, Bastarache Lisa, He Jing, Lewis Adam, Aka Ida T, Shotwell Matthew S, Reddy Srijaya K, Hogan Kirk J, Biesecker Leslie G, Kertai Miklos D
Division of Pediatric Anesthesiology, Monroe Carell Jr. Children's Hospital.
Department of Anesthesiology, Vanderbilt University Medical Center.
Pharmacogenet Genomics. 2025 Feb 1;35(2):65-72. doi: 10.1097/FPC.0000000000000551. Epub 2025 Jan 2.
We aimed to classify genetic variants in RYR1 and CACNA1S associated with malignant hyperthermia using biobank genotyping data in patients exposed to triggering anesthetics without malignant hyperthermia phenotype.
We identified individuals who underwent surgery and were exposed to triggering anesthetics without malignant hyperthermia phenotype and who had RYR1 or CACNA1S genotyping data available in our biobank. We classified all variants in the cohort using a Bayesian framework of the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists guidelines for variant classification and updated the posterior probabilities from this model with the new information from our biobank cohort.
We identified 253 patients with 95 RYR1 variants and 12 CACNA1S variants. After applying a Bayesian framework, we classified 17 variants as benign (B), 31 as likely benign (LB), 57 as uncertain (VUS), and 2 as likely pathogenic (LP). When we incorporated evidence about unique exposures to malignant hyperthermia triggering anesthetic agents, 48 of 107 (45%) variants were downgraded (9 to B, 37 to LB, and 2 to VUS). Notably, 41 (72%) of 57 VUSs were downgraded to B or LB. When repeat anesthetics in the same individual were counted as one exposure, 42 of 107 (39%) of variants were downgraded (5 to B, 35 to LB, and 2 to VUS). Specifically, 37 (65%) of 57 VUSs were downgraded to LB.
Deidentified biorepositories linked with anesthetic data offer a new method of integrating clinical evidence into the assessment of variant probability of pathogenicity.
我们旨在利用生物样本库基因分型数据，对暴露于触发麻醉剂但无恶性高热表型的患者中与恶性高热相关的RYR1和CACNA1S基因变异进行分类。
我们识别出接受手术且暴露于触发麻醉剂但无恶性高热表型、并在我们的生物样本库中有RYR1或CACNA1S基因分型数据的个体。我们使用美国医学遗传学与基因组学学会和分子病理学家协会的变异分类贝叶斯框架对队列中的所有变异进行分类，并根据我们生物样本库队列的新信息更新该模型的后验概率。
我们识别出253例患者，其中有95个RYR1变异和12个CACNA1S变异。应用贝叶斯框架后，我们将17个变异分类为良性（B），31个为可能良性（LB），57个为不确定（VUS），2个为可能致病（LP）。当我们纳入关于恶性高热触发麻醉剂独特暴露的证据时，107个变异中的48个（45%）被降级（9个降至B，37个降至LB，2个降至VUS）。值得注意的是，57个VUS中有41个（72%）被降级为B或LB。当将同一个体的重复麻醉视为一次暴露时，107个变异中的42个（39%）被降级（5个降至B，35个降至LB，2个降至VUS）。具体而言，57个VUS中有37个（65%）被降级为LB。
与麻醉数据相关联的去识别生物样本库提供了一种将临床证据整合到致病性变异概率评估中的新方法。
