The Genetic Landscape of Hypoplastic Left Heart Syndrome.
The Genetic Landscape of Hypoplastic Left Heart Syndrome.
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左心脏综合征的遗传景观。
DOI：
10.1007/s00246-018-1861-4
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发表时间：
2018-08
影响因子：
1.6
通讯作者：
Lo CW
中科院分区：
文献类型：
--
作者：
Yagi H;Liu X;Gabriel GC;Wu Y;Peterson K;Murray SA;Aronow BJ;Martin LJ;Benson DW;Lo CW
左心发育不良综合征（HLHS）是最致命的先天性心脏病之一，临床上仍具有挑战性。虽然手术姑息治疗使大多数HLHS患者能够以单心室生理学存活下来，但许多患者将遭受心力衰竭，需要心脏移植作为唯一的治疗过程。目前的范式表明HLHS主要是血液动力学起源，但最近的研究结果分析的第一个小鼠模型HLHS显示内在的心肌细胞增殖和分化缺陷的左心室（LV）发育不全。右心室中严重程度较低的类似缺陷的发现表明，这可能有助于手术缓解HLHS患者的心力衰竭风险。对8个独立的HLHS小鼠品系的分析表明，HLHS在病因学上是遗传异质性和多基因的。对Ohia小鼠系的详细分析以及CRISPR基因靶向小鼠的验证研究揭示了HLHS的双基因病因学。HDAC阻遏物复合物的一个组成部分Sap130的突变被证明是驱动LV发育不全的原因，而原钙粘蛋白细胞粘附分子Pcdha9的突变在HLHS相关的瓣膜缺陷中发挥了关键作用。基于这些发现，我们提出了一个新的范例，其中复杂的冠心病，如HLHS可能会出现在一个模块化的方式，介导的多个突变。内在心肌细胞缺陷的发现提示血流动力学干预可能不能挽救LV生长。HLHS的深刻遗传异质性和寡基因病因表明，HLHS的遗传格局可能是复杂的，更容易在临床研究中建立一个家族性研究设计。
Hypoplastic left heart syndrome (HLHS) is one of the most lethal congenital heart defects, and remains clinically challenging. While surgical palliation allows most HLHS patients to survive their critical heart disease with a single-ventricle physiology, many will suffer heart failure, requiring heart transplantation as the only therapeutic course. Current paradigm suggests HLHS is largely of hemodynamic origin, but recent findings from analysis of the first mouse model of HLHS showed intrinsic cardiomyocyte proliferation and differentiation defects underlying the left ventricular (LV) hypoplasia. The findings of similar defects of lesser severity in the right ventricle suggest this could contribute to the heart failure risks in surgically palliated HLHS patients. Analysis of 8 independent HLHS mouse lines showed HLHS is genetically heterogeneous and multigenic in etiology. Detailed analysis of the Ohia mouse line accompanied by validation studies in CRISPR gene-targeted mice revealed a digenic etiology for HLHS. Mutation in Sap130, a component of the HDAC repressor complex, was demonstrated to drive the LV hypoplasia, while mutation in Pcdha9, a protocadherin cell adhesion molecule played a pivotal role in the valvular defects associated with HLHS. Based on these findings, we propose a new paradigm in which complex CHD such as HLHS may arise in a modular fashion, mediated by multiple mutations. The finding of intrinsic cardiomyocyte defects would suggest hemodynamic intervention may not rescue LV growth. The profound genetic heterogeneity and oligogenic etiology indicated for HLHS would suggest that the genetic landscape of HLHS may be complex and more accessible in clinical studies built on a familial study design.
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