Novel Insights into the Etiology, Genetics, and Embryology of Hypoplastic Left Heart Syndrome.
Novel Insights into the Etiology, Genetics, and Embryology of Hypoplastic Left Heart Syndrome.
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DOI：
10.1177/21501351221102961
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发表时间：
2022-09
影响因子：
0.9
通讯作者：
Lo, Cecilia W.
中科院分区：
文献类型：
--
作者：
Gabriel, George C.;Yagi, Hisato;Xu, Xinxiu;Lo, Cecilia W.
关键词：
左心发育不良综合征（HLHS）是一种相对罕见的严重先天性心脏缺陷（CHD），与其他左心室流出道（LVOT）病变密切相关，包括最常见的心脏缺陷之一的二叶式主动脉瓣（BAV）。虽然HLHS、BAV和其他LVOT病变具有很强的遗传基础，但其遗传病因仍知之甚少。大规模小鼠突变筛选的结果显示HLHS具有多基因病因学，并且是遗传异质性的，这解释了识别HLHS遗传原因的困难。在Ohia小鼠中，HLHS显示不完全的迁移。一些小鼠表现出小LV和正常主动脉，而另一些小鼠表现出正常LV和发育不良主动脉，表明LV发育不良不是血流动力学驱动的。在Ohia突变体中，发现HLHS具有双基因模块化结构，染色质修饰剂突变导致小LV表型，Pcdha 9突变导致主动脉/主动脉瓣发育不全。单独的Pcdha 9突变可以引起BAV，并且在人类基因组中，跨越PCDHA 7 -10的两个常见缺失拷贝数变体与BAV相关。因此，HLHS的二基因病因学可以解释HLHS（一种罕见的CHD）与BAV（最常见的CHD之一）的密切关系。Ohia HLHS心脏组织的功能分析显示，小LV中存在严重的线粒体功能障碍，而正常大小的RV也受到影响，但较轻，这表明手术缓解的HLHS患者对心力衰竭的脆弱性可能起作用。这些研究结果表明，对HLHS遗传学的深入了解可能会产生新的治疗方法，以改善HLHS患者的预后。
Hypoplastic left heart syndrome (HLHS) is a relatively rare severe congenital heart defect (CHD) closely linked to other left ventricular outflow tract (LVOT) lesions including bicuspid aortic valve (BAV), one of the most common heart defects. While HLHS, BAV, and other LVOT lesions have a strong genetic underpinning, their genetic etiology remains poorly understood. Findings from a large-scale mouse mutagenesis screen showed HLHS has a multigenic etiology and is genetically heterogenous, explaining difficulties in identifying the genetic causes of HLHS. In Ohia mice, HLHS shows incomplete penetrance. Some mice exhibited small LV with normal aorta, and others a normal LV with hypoplastic aorta, indicating the LV hypoplasia is not hemodynamically driven. In Ohia mutants, HLHS was found to have a digenic modular construction, with mutation in a chromatin modifier causing the small LV phenotype and mutation in Pcdha9 causing the aorta/aortic valve hypoplasia. The Pcdha9 mutation alone can cause BAV, and in the human genome two common deletion copy number variants spanning PCDHA7–10 are associated with BAV. Hence the digenic etiology of HLHS can account for the close association of HLHS, a rare CHD, with BAV, one of the most common CHD. Functional analysis of Ohia HLHS heart tissue showed severe mitochondrial dysfunction in the small LV, while the normal size RV is also affected but milder, suggesting possible role in vulnerability of surgically palliated HLHS patients to heart failure. These findings suggest insights into the genetics of HLHS may yield new therapies for improving outcome for patients with HLHS.
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影响因子：
2.6
作者：
Best KE;Miller N;Draper E;Tucker D;Luyt K;Rankin J
通讯作者：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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影响因子：
3.4
作者：
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通讯作者：
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DOI：
10.1016/j.jtcvs.2009.04.061
发表时间：
2010-01-01
影响因子：
6
作者：
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通讯作者：
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