Genetics of Hypoplastic Left Heart Syndrome

左心发育不良综合征的遗传学

基本信息

批准号：
9324048
负责人：
Daniel Bernstein
金额：
$ 49.3万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
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/9324048
关键词：
Affect Anatomy Child Comorbidity Congenital Abnormality Corpus Callosum DNA Data Defect Deformity Development Disease Enrollment Etiology First Degree Relative Genetic Genetic Predisposition to Disease Goals 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 aortic valve aortic valve disorder axonal pathfinding 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 public health relevance

项目摘要

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（由适用提供）：先天性心脏病（CHD）是最常见的先天缺陷，也是儿童发病率和死亡率的主要原因。尽管已经确定了某些类型的冠心病的遗传原因，但大多数形式的零星心脏病的基础仍然未知。在各种形式的冠心病中，低塑性左心综合征（HLHS）似乎具有特别高的遗传力，并且通常与一级亲属中的临床主动脉瓣疾病有关。相关的主要合并症之一与CHD，尤其是HLHS有关，涉及不良的神经发育结果。虽然病因尚不清楚，但有证据表明神经系统成果的“患者内在”成分通常是微妙的，并且在学龄前是呈现的。 HLHS患者，尤其是起源或call体性疾病的患者，神经 - 动物学异常的发生率也增加了，但是这种遗传基础尚不清楚，并且尚不清楚神经系统疾病是否与解剖学异常有关。在该提案的主要项目中，我们旨在检验HLHS的假设，即HLHS源于具有相对较强效应的遗传变异，并且至少在一部分情况下，相同的遗传变异中断了阳性瓣膜和神经发育。通过评估HLHS和神经 - 动物异常作为独特的“综合征”的组合，即使在索引病例无关的情况下，我们也可以在这个更均匀的子集中识别出常见的遗传病因。在相关的神经发育项目中，我们将检验以下假设：HLHS中不良神经发育结果具有遗传成分，并且可能与神经 - 动物学缺陷有关。为了实现这些目标，我们计划执行以下操作：1）通过MRI来招募HLHS并收集DNA，表型数据，确定临界神经系统解剖学，并评估其神经发育结果； 2）通过下一代测序确定与HLHS相关的下一代测序，而HLHS有或没有共存的解剖神经发育异常和/或神经发育结果异常； 3）通过实验确定与HLHS分离或神经发育结果分离的遗传变异是否会改变功能，并通过使用人类诱导的多能STEM（IPS）细胞（IPS）细胞和最新的前期基因组编辑技术来促进与疾病相关的病理。这些目标将通过两个综合项目来追求，这些项目研究相同的患者队列并利用每个患者的数据，以发现HLHS的遗传原因和相关的较差的神经发育结果。我们已经组建了一个心脏病专家，神经发育专家，遗传学家和计算生物学家，在UCSF，Gladstone和Stanford实现了这些目标，这些目标只能在国家财团的背景下完成。