Genetics of Hypoplastic Left Heart Syndrome

 描述(申请人提供)：先天性心脏病(CHD)是最常见的出生缺陷，也是导致儿童发病和死亡的主要原因。虽然某些类型的CHD的遗传原因已经确定，但大多数形式的散发性心脏病的基础仍不清楚。在各种形式的冠心病中，左心发育不良综合征(HLHS)具有特别高的遗传性，并经常与一级亲属的亚临床主动脉瓣疾病相关。与此相关的主要并发症之一 患有CHD，尤其是HLHS，涉及到较差的神经发育结果。虽然病因尚不清楚，但有证据表明，神经学结果中存在“患者固有的”成分，这通常是微妙的，出现在学龄期。HLHS患者中神经解剖异常的发生率也增加，特别是胼胝体发育不全或发育不全，但其遗传学基础尚不清楚，也不清楚不良的神经结局是否与解剖异常有关。在这项提案的主要项目中，我们的目标是检验这样的假设，即HLHS是由具有相对较强影响的遗传变异产生的，并且在至少一个子集的情况下，相同的遗传变异会破坏 主动脉瓣和神经元的发育。通过评估HLHS和神经解剖异常的组合作为一种独特的“综合征”，我们可以在这个更同质的子集中识别出共同的遗传病因，即使指标病例是无关的。在相关的神经发育项目中，我们将检验这一假设，即HLHS的不良神经发育结果具有遗传成分，并可能独立地与神经解剖缺陷相关。为了实现这些目标，我们计划做以下工作：1)招募HLHS患者并收集DNA、表型数据，通过MRI确定亚临床神经解剖学，并评估他们的神经发育结果；2)通过下一代测序确定与HLHS相关的基因变量，无论是否共存解剖神经发育异常和/或异常神经发育结果；3)通过实验确定分离HLHS或神经发育结果不良的基因变量是否正在改变功能，并通过使用人类诱导多能干细胞(IPS)细胞和最先进的基因组编辑技术来促成与疾病相关的病理。这些目标将通过两个综合项目来实现，这两个项目研究相同的患者队列，并利用每个项目的数据来发现HLHS的遗传原因和相关的神经发育不良结果。我们组建了一个由加州大学旧金山分校、格拉德斯通大学和斯坦福大学的心脏病专家、神经发育专家、遗传学家和计算生物学家组成的团队来实现这些目标，这些目标只有在国家联盟的背景下才能实现。

 DESCRIPTION (provided by applicant): Congenital heart disease (CHD) is the most common birth defect and a leading cause of morbidity and mortality in children. While the genetic cause of some types of CHD has been identified, the basis for most forms of sporadic heart disease remains unknown. Among the various forms of CHD, hypoplastic left heart syndrome (HLHS) appears to have a particularly high degree of heritability and is often associated with sub- clinical aortic valve disease in first-degree relatives. One of the major co-morbidities associated with CHD, and particularly HLHS, involves poor neurodevelopmental outcomes. While the etiology remains unclear, there is evidence to support a "patient-intrinsic" component to the neurologic outcome, which often is subtle and presents at school age. There is also an increased incidence of neuro-anatomic abnormalities in patients with HLHS, particularly agenesis or hypoplasia of the corpus callosum, but the genetic basis for this is unclear and it is unknown if poor neurologic outcomes are related to anatomic anomalies. In the Main Project of this proposal, we aim to test the hypothesis that HLHS arises from genetic variants with relatively strong effects and that in at least a subset of cases, the same genetic variants disrupt both aortic valve and neuronal development. By evaluating the combination of HLHS and neuro-anatomic anomalies as a unique "syndrome", we may identify a common genetic etiology within this more homogeneous subset even when index cases are unrelated. In the associated Neurodevelopmental Project, we will test the hypothesis that adverse neurodevelopmental outcomes in HLHS have a genetic component and may independently be associated with neuro-anatomic defects. To achieve these goals, the we plan to do the following: 1) Enroll subjects with HLHS and collect DNA, phenotypic data, determine sub-clinical neurologic anatomies by MRI, and assess their neurodevelopmental outcomes; 2) Determine genetic variants through next-generation sequencing that are associated with HLHS with or without co-existence of anatomic neurodevelopmental anomalies and/or abnormal neurodevelopmental outcomes; 3) Experimentally determine if genetic variants that segregate with HLHS or with poor neurodevelopmental outcomes are function-altering and contribute to pathologies associated with disease by using human induced pluripotent stem (iPS) cells and state-of-the-art genome editing techniques. These aims will be pursued through two integrated projects that study the same cohort of patients and leverage data from each to discover genetic causes of HLHS and the associated poor neurodevelopmental outcomes. We have assembled a team of cardiologists, neurodevelopmental experts, geneticists, and computational biologists at UCSF, Gladstone, and Stanford to accomplish these goals, which could only be accomplished in the context of a national consortium.