Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment
Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment
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DOI：
10.1038/gim.2013.138
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发表时间：
2014-04-01
影响因子：
8.8
通讯作者：
Semsarian, Christopher
中科院分区：
文献类型：
--
作者：
Das, Jipin K.;Ingles, Jodie;Semsarian, Christopher
目的：肥厚型心肌病基因检测的认识和临床应用已取得重大进展。确定单核苷酸变异的致病性仍然是一个主要的临床挑战。本研究旨在重新评估肥厚型心肌病先证者的单核苷酸变异分类。方法：包括已报道的致病突变或变异意义不确定的肥厚型心肌病先证者。获得家族史和病史。结果：从2000年到2012年，共有136名无关的肥厚型心肌病先证者进行了基因检测，其中63人(46%)携带至少一个致病突变：MYBPC3(n=34；47%)。MYH7(n=23；32%)基因变异共占79%。对6个先证者(10%)的5个变异进行了重新分类：2个未知意义的变异升级为致病，1个未知意义的变异和1个致病变异降级为良性，1个致病变异(发现于2个家系)降级为未知意义的变异。结论：鉴于疾病和正常人群中可获得的遗传信息的快速增长，定期重新评估单核苷酸变异数据对于肥厚型心肌病是必不可少的。
Purpose: Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands.Methods: Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current population, based allele frequencies.Results: From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing; of which 63 (46%) carried a least one pathogenic mutation: MYBPC3 (n = 34; 47%). and MYH7 (n = 23; 32%) gene variants together accounted for 79%.; Five variants in six probands (10%) Were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of Uncertain significance. None of the reclassifications had any adverse clinical consequences.Conclusion: Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.