Genetics of Hypoplastic Left Heart Syndrome

 描述（由申请人提供）：先天性心脏病（CHD）是最常见的出生缺陷，也是儿童发病率和死亡率的主要原因。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然未知。在各种形式的CHD中，左心发育不良综合征（HLHS）似乎具有特别高的遗传性，并且通常与一级亲属中的亚临床主动脉瓣疾病相关。其中一种主要的合并症 CHD，特别是HLHS，涉及不良的神经发育结果。虽然病因尚不清楚，但有证据支持神经系统结局的“患者内在”成分，这通常是微妙的，并在学龄时出现。HLHS患者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，但其遗传基础尚不清楚，也不清楚不良的神经功能结局是否与解剖异常相关。在本提案的主要项目中，我们的目标是测试以下假设：HLHS是由具有相对较强影响的遗传变异引起的，并且至少在一部分情况下，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个独特的“综合征”，我们可以确定一个共同的遗传病因在这个更同质的子集，即使索引案件是无关的。在相关的神经发育项目中，我们将检验这一假设，即HLHS的不良神经发育结局具有遗传成分，并且可能独立地与神经解剖缺陷相关。为了实现这些目标，我们计划进行以下工作：1）招募HLHS受试者并收集DNA、表型数据，通过MRI确定亚临床神经解剖结构，并评估其神经发育结局; 2）通过下一代测序确定与HLHS相关的遗传变异，伴或不伴解剖神经发育异常和/或异常神经发育结局; 3）通过使用人类诱导多能干细胞（iPS）和最先进的基因组编辑技术，通过实验确定与HLHS分离或神经发育结果较差的遗传变异是否会改变功能并导致与疾病相关的病理。这些目标将通过两个综合项目来实现，这两个项目研究同一组患者，并利用每个患者的数据来发现HLHS的遗传原因和相关的不良神经发育结果。为了实现这些目标，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。

 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.