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首页> 外文期刊>Medicine. >Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy
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Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy

机译：下一代测序鉴定了具有肥厚性心肌病的血液中患者中的致病和改性剂突变

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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.
机译：肥厚性心肌病（HCM）是一种高度异质的疾病，呈现相当大的恐育和患有型植物型变异，包括疾病严重程度，发病年龄和疾病进展。这种糟糕的差异引发了遗传改性效应的可能性，特别是在myBPC3 - 分配的HCM中。在一个大型血缘患有中国HCM家族中，我们确定了8名成员，涉及MYBPC3 C.3624DELC（P.LYS1209SERFS）疾病引起的突变，但具有非常不同的表型。基因分型排除了先前描述的肾素 - 血管紧张素 - 醛固酮体系中的改变效果。然后，通过进行靶向的下一代测序，我们通过进行靶向下一代测序筛选所有已知导致基因和心肌病和通道病变的密切相关基因的改变变体。首次，我们表明，在所有严重影响的HCM患者中存在C.1598C> T（P.SER533Leu）突变，但在所有严重影响的HCM患者中存在，但在适度影响的那些中，存在于所有严重影响的HCM患者中或基因型阳性表型阴性患者。这种CaCnB2 p.ser533Leu突变在进化中极为保守，并且在550个健康对照中没有发现。我们的研究结果表明，CACNB2是MYBPC3 -Asocationalial HCM的可能候选遗传改性剂，但需要更多的遗传证据和功能实验来确认。

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