Gao Guangyuan, Liu Guohui, Chen Weiwei, Tong Yaliang, Mao Cuiying, Liu Jinsha, Zhang Xing, He Max M, Yang Ping
Department of Cardiology, China-Japan Union Hospital of Jilin University.
Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, Changchun.
Medicine (Baltimore). 2020 Aug 21;99(34):e21843. doi: 10.1097/MD.0000000000021843.
Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease and a common cause of sudden cardiac death, heart failure, atrial fibrillation and stroke. In families affected by HCM, genotyping is useful for identifying susceptible relatives. In the present study, we investigated the disease-causing mutations in a three-generation Chinese family with HCM using whole exome sequencing (WES).
The proband, a 50-year-old man, was diagnosed with HCM at the age of 41 years. He presented with an asymmetric hypertrophic interventricular septum and a maximum interventricular septum thickness of 18.04 mm. His third elder sister, niece and daughter were also clinically affected by HCM.
Autosomal dominant HCM.
Seven family members, including 4 affected members, accepted WES. The genetic variants were subsequently called using Genome Analysis Toolkit and annotated using the InterVar program. Following frequency filtration by the Genome Aggregation Database, the variants were evaluated using an in-house bioinformatics analysis pipeline.
HCM was transmitted as an autosomal dominant trait in the family. An extremely rare stop gained mutation, rs796925245 (g.1:201359630G>A, c.835C>T, p.Gln279Ter) in the troponin T2 (TNNT2) gene was identified as the disease-causing mutation. The stop gained mutation was predicted to result in a truncated troponin T protein in cardiac sarcomere. An adolescent family member who had normal echocardiographic measurements was found to carry the same disease-causing mutation.
A novel nonsense TNNT2 mutation was identified as the HCM-causing mutation in this Chinese pedigree. Since HCM shows a low penetrance by clinical criteria in adolescents, the adolescent mutation carrier, who is still clinically unaffected, should be offered routine follow-ups and sport activity recommendations to prevent adverse events including sudden cardiac death in the future.
肥厚型心肌病（HCM）是一种遗传性心肌疾病，是心源性猝死、心力衰竭、心房颤动和中风的常见病因。在受HCM影响的家族中，基因分型有助于识别易感亲属。在本研究中，我们使用全外显子组测序（WES）研究了一个三代中国HCM家族中的致病突变。
先证者为一名50岁男性，41岁时被诊断为HCM。他表现为不对称性肥厚的室间隔，最大室间隔厚度为18.04毫米。他的三姐、侄女和女儿也有HCM的临床症状。
常染色体显性HCM。
七名家庭成员，包括四名受影响成员，接受了WES。随后使用基因组分析工具包对基因变异进行分型，并使用InterVar程序进行注释。在通过基因组聚合数据库进行频率过滤后，使用内部生物信息学分析流程对变异进行评估。
HCM在该家族中以常染色体显性性状遗传。在肌钙蛋白T2（TNNT2）基因中发现了一个极其罕见的获得性终止突变，rs796925245（g.1:201359630G>A，c.835C>T，p.Gln279Ter），被确定为致病突变。该获得性终止突变预计会导致心肌肌节中的肌钙蛋白T蛋白截短。一名超声心动图测量正常的青少年家庭成员被发现携带相同的致病突变。
在这个中国家系中，一个新的TNNT2无义突变被确定为导致HCM的突变。由于根据临床标准，HCM在青少年中的外显率较低，对于仍未出现临床症状的青少年突变携带者，应提供常规随访和体育活动建议，以预防未来包括心源性猝死在内的不良事件。
