Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy.
Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy.
复制标题
下一代测序鉴定了一个患有肥厚型心肌病的中国近亲家族的致病突变和修饰突变
DOI：
10.1097/md.0000000000007010
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发表时间：
2017-06
期刊：
影响因子：
1.6
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Zhang X;Xie J;Zhu S;Chen Y;Wang L;Xu B
肥厚性心肌病（HCM）是一种高度异质性的疾病，表现出相当大的家族间和家族内表型变异，包括疾病严重程度、发病年龄和疾病进展。这种鲜为人知的变异增加了基因修饰效应的可能性，特别是在mybpc3相关的HCM中。在一个大型的中国HCM家族中，我们发现8个成员携带MYBPC3 c.3624delC （p.Lys1209Serfs）致病突变，但表型非常不同。基因分型排除了先前描述的肾素-血管紧张素-醛固酮系统变异的修饰作用。随后，我们通过进行有针对性的下一代测序，筛选了所有已知的心肌病和通道病的致病基因和密切相关基因的修饰变异。我们首次发现电压依赖性l型钙通道亚基β -2 （CACNB2）中的c.1598C>T （p.Ser533Leu）突变存在于所有重度HCM患者中，而不存在于中度HCM患者或基因型阳性表型阴性患者中。这种CACNB2 p.Ser533Leu突变在进化中非常保守，在550名健康对照中未发现。我们的研究结果表明，CACNB2可能是mybpc3相关家族性HCM的候选遗传修饰因子，但需要更多的遗传证据和功能实验来证实。
Abstract Hypertrophic cardiomyopathy (HCM) is a highly heterogeneous disease displaying considerable interfamilial and intrafamilial phenotypic variation, including disease severity, age of onset, and disease progression. This poorly understood variance raises the possibility of genetic modifier effects, particularly in MYBPC3-associated HCM. In a large consanguineous Chinese HCM family, we identified 8 members harboring the MYBPC3 c.3624delC (p.Lys1209Serfs) disease-causing mutation, but with very disparate phenotypes. Genotyping ruled out the modifying effect of previously described variants in renin-angiotensin-aldosterone system. Afterwards, we screened for modifying variants in all known causing genes and closely related genes for cardiomyopathy and channelopathy by performing targeted next-generation sequencing. For first time, we showed that a c.1598C>T (p.Ser533Leu) mutation in voltage-dependent l-type calcium channel subunit beta-2 (CACNB2) was present in all severely affected HCM patients, but not in those moderately affected or genotype-positive phenotype-negative patients. This CACNB2 p.Ser533Leu mutation is extremely conserved in evolution, and was not found in 550 healthy controls. Our results suggest that CACNB2 is a possible candidate genetic modifier of MYBPC3-associated familial HCM, but more genetic evidence and functional experiments are needed to confirm.