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.
复制标题
DOI：
10.1038/s41431-021-00954-2
复制
发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Stefansson K
中科院分区：
文献类型：
--
作者：
Fridriksdottir R;Jonsson AJ;Jensson BO;Sverrisson KO;Arnadottir GA;Skarphedinsdottir SJ;Katrinardottir H;Snaebjornsdottir S;Jonsson H;Eiriksson O;Oskarsson GR;Oddsson A;Jonasdottir A;Jonasdottir A;Sigurdsson GH;Indridason EP;Sigurdsson SB;Bjornsdottir G;Saemundsdottir J;Magnusson OT;Bjornsson HT;Thorsteinsdottir U;Sigurdsson TS;Sulem P;Sigurdsson MI;Stefansson K
恶性高热（MH）易感性是一种罕见的危及生命的疾病，发生在暴露于触发剂。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中的致病性和可能致病性变体时，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，我们报告了一名疑似MH事件的10岁冰岛先证者，携带杂合错义变体NM_000540.2：c.6710G> A r。（6710g> a）p.（Cys2237Tyr）在RYR1基因，可能是致病性的。该变异是一个三代家庭中的四个人所独有的，并且在62，240名全基因组测序（WGS）冰岛人中缺失。单倍型共享和WGS显示，该变异发生为体细胞嵌合体，也存在于先证者的祖父的种系中。其次，使用一组62，240名患有WGS的冰岛人，我们评估了RYR1和CACNA1S中可操作的致病性和可能致病性变体的携带频率。根据ClinVar分类，我们观察到43名冰岛人携带的RYR1中有13种可操作的变体，而CACNA1S中没有可操作的变体。每1450名冰岛人中就有一人携带可采取行动的MH变体。广泛的测序允许更好地分类和精确的变异日期，并且大部分人群的WGS已经导致了可操作的MH基因型的偶然发现。
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.
登录
查看更多内容
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
DOI：
10.1038/gim.2013.73
发表时间：
2013-07
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.8
作者：
McLaren, William;Pritchard, Bethan;Cunningham, Fiona
通讯作者：
Cunningham, Fiona
DOI：
10.1038/gim.2015.187
发表时间：
2016-09
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Carey DJ;Fetterolf SN;Davis FD;Faucett WA;Kirchner HL;Mirshahi U;Murray MF;Smelser DT;Gerhard GS;Ledbetter DH
通讯作者：
Ledbetter DH
影响因子：
8.8
作者：
Fiszer D;Shaw MA;Fisher NA;Carr IM;Gupta PK;Watkins EJ;Roiz de Sa D;Kim JH;Hopkins PM
通讯作者：
Hopkins PM