Hypoplastic Left Heart Syndrome Sequencing Reveals a Novel NOTCH1 Mutation in a Family with Single Ventricle Defects.
Hypoplastic Left Heart Syndrome Sequencing Reveals a Novel NOTCH1 Mutation in a Family with Single Ventricle Defects.
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DOI：
10.1007/s00246-017-1650-5
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发表时间：
2017-08
影响因子：
1.6
通讯作者：
Hong CC
中科院分区：
文献类型：
--
作者：
Durbin MD;Cadar AG;Williams CH;Guo Y;Bichell DP;Su YR;Hong CC
左心发育不全综合征(HLHS)与12个候选基因的胚系突变和HAND1基因的一个复发性体细胞突变有关。通过对HLHS患者的心脏组织样本进行靶向和整体外显子组测序(WES)，我们试图评估与HLHS相关的体细胞和生殖系突变的流行率。我们对14例HLHS患者的心脏标本(9例LV和5例RV)以及4例LV、2例主动脉和4例匹配的PBMC的WES进行了HAND1基因的Sanger测序，分析其序列差异。我们还筛查了与HLHS有关的12个候选基因的突变。我们在我们的HLHS队列中没有发现体细胞突变。然而，我们在一名既有HLHS家族史又有右心发育不良综合征(HRHs)的HLHS患者中发现了NOTCH1的一种新的胚系移码/停止-获得突变。我们的研究涉及与特定突变相关的首批单脑室缺陷家族病例之一，加强了NOTCH1突变与HLHS的关联，并提示两种形态上不同的单脑室疾病，HLHS和HRHs，可能具有共同的分子和细胞病因学。最后，LV的体细胞突变不太可能导致HLHS。
Hypoplastic left heart syndrome (HLHS) has been associated with germline mutations in 12 candidate genes and a recurrent somatic mutation in HAND1 gene. Using targeted and whole exome sequencing (WES) of heart tissue samples from HLHS patients, we sought to estimate the prevalence of somatic and germline mutations associated with HLHS. We performed Sanger sequencing of the HAND1 gene on 14 ventricular (9 LV and 5 RV) samples obtained from HLHS patients, and WES of 4 LV, 2 aortic and 4 matched PBMC samples, analyzing for sequence discrepancy. We also screened for mutations in the 12 candidate genes implicated in HLHS. We found no somatic mutations in our HLHS cohort. However, we detected a novel germline frameshift/stop-gain mutation in NOTCH1 in a HLHS patient with a family history of both HLHS and hypoplastic right heart syndrome (HRHS). Our study, involving one of the first familial cases of single ventricle defects linked to a specific mutation, strengthens the association of NOTCH1 mutations with HLHS, and suggests that the two morphologically distinct single ventricle conditions, HLHS and HRHS, may share a common molecular and cellular etiology. Finally, somatic mutations in the LV are an unlikely contributor to HLHS.
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影响因子：
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