Genetics of Hypoplastic Left Heart Syndrome

左心发育不良综合征的遗传学

• 批准号: 9114658
• 负责人: Daniel Bernstein
• 金额: $ 49.32万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114658
• 关键词: Affect; Anatomy; Child; Clinical; Comorbidity; Congenital Abnormality; Corpus Callosum; DNA; Data; Defect; Deformity; Development; Disease; Enrollment; Etiology; First Degree Relative; Genetic; Genetic Predisposition to Disease; Goals; Health; Heart Diseases; Heritability; Human; Hypoplastic Left Heart Syndrome; Incidence; Magnetic Resonance Imaging; Morbidity - disease rate; Mutation; NOTCH1 gene; Neurodevelopmental Disorder; Neurologic; Neurological outcome; Outcome; Pathology; Patients; Performance; Reporting; School-Age Population; Schools; Syndrome; Techniques; Testing; abstracting; aortic valve; aortic valve disorder; axonal pathfinding; base; bicuspid aortic valve; cognitive function; cohort; congenital heart disorder; genetic variant; genome editing; indexing; induced pluripotent stem cell; mortality; myelination; neuron development; next generation sequencing; phenotypic data

 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.

 描述（由申请人提供）：先天性心脏病（CHD）是最常见的出生缺陷，也是儿童发病和死亡的主要原因。虽然某些类型的先心病的遗传原因已被确定，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，左心发育不全综合征 (HLHS) 似乎具有特别高的遗传性，并且通常与一级亲属的亚临床主动脉瓣疾病相关。相关的主要并发症之一 CHD，尤其是 HLHS，会导致神经发育结果不佳。虽然病因尚不清楚，但有证据支持神经系统结果存在“患者固有”成分，这种成分通常很微妙，并在学龄时出现。 HLHS 患者神经解剖异常的发生率也有所增加，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系统结果是否与解剖异常有关。在本提案的主要项目中，我们旨在检验以下假设：HLHS 是由具有相对较强影响的遗传变异引起的，并且至少在一部分病例中，相同的遗传变异会破坏 主动脉瓣和神经元发育。通过将 HLHS 和神经解剖异常的组合评估为独特的“综合征”，即使指标病例不相关，我们也可以在这个更同质的子集中识别出共同的遗传病因。在相关的神经发育项目中，我们将检验以下假设：HLHS 的不良神经发育结果具有遗传成分，并且可能与神经解剖缺陷独立相关。为了实现这些目标，我们计划做以下工作：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果； 2) 通过下一代测序确定与 HLHS 相关的遗传变异，无论是否共存解剖神经发育异常和/或神经发育结果异常； 3) 通过使用人类诱导多能干 (iPS) 细胞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 的遗传原因以及相关的不良神经发育结果。我们在加州大学旧金山分校、格拉德斯通和斯坦福大学组建了一支由心脏病专家、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，而这些目标只能在国家联盟的背景下才能实现。