Genetic Contributions to Valvar Pulmonary Stenosis

瓣膜肺动脉狭窄的遗传因素

• 批准号: 10668443
• 负责人: Kathryn Nicole Weaver
• 金额: $ 15.9万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668443
• 关键词: Address; Affect; Candidate Disease Gene; Cardiac; Cardiac Surgery procedures; Child; Complex; Congenital Abnormality; Copy Number Polymorphism; Data; Data Analyses; Data Set; Development; Diagnosis; Early Diagnosis; Etiology; Evaluation; Family; Frequencies; Future; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genome; Genomics; Goals; Health; Healthcare; Heart Abnormalities; Heritability; Incidence; Individual; Infant; Intervention; Investigation; Knowledge; Lesion; Live Birth; Medical Care Team; Noonan Syndrome; Obstruction; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Pulmonary Valve Stenosis; Recommendation; Recurrence; Retrospective Studies; Risk; Single Nucleotide Polymorphism; Stenosis; Testing; Variant; Ventricular; autosome; care burden; causal variant; cohort; congenital heart disorder; evaluation/testing; exome; genetic disorder diagnosis; genetic testing; genetic variant; genome sequencing; genome wide association study; genome-wide; health determinants; improved; novel; proband; rare variant; repaired; routine care; whole genome

ABSTRACT Congenital heart disease (CHD) is the most common class of birth defects, occurring in 1 in 100 live births, and is known to have both Mendelian and complex genetic etiologies. There are multiple studies investigating genetic contributions to specific types of CHD, but right ventricular outflow tract lesions are missing or underrepresented in such studies. Valvar pulmonary stenosis (vPS), a type of right ventricular outflow tract obstruction, accounts for ~10% of CHD. One quarter of individuals with vPS require invasive treatment with balloon valvuloplasty and/or open heart surgical repair, and a subset of these will require repeat intervention for recurrent valve stenosis, or to repair valve insufficiency/regurgitation. Thus, a diagnosis of vPS represents a significant lifetime healthcare burden. Our single-center retrospective study demonstrated that 10% of 204 probands with vPS carried a genetic diagnosis, but only 18% of the cohort had received genetic evaluation and/or testing (Anderson et al 2019). In contrast, our unpublished analysis of 123 sequenced (exome or genome) probands with vPS identified a Mendelian diagnosis in 17%. Noonan syndrome, an autosomal dominant condition with variable expression, was the most common diagnosis identified in both cohorts. In both groups, there was a high frequency of coexisting extracardiac and/or neurodevelopmental anomalies among children without a genetic diagnosis. In sum, this is highly suggestive that Mendelian diagnoses are under-recognized among individuals with vPS, and that there are novel causative genes yet to be identified. Further, studies of familial recurrence of right ventricular outflow tract obstructive CHD identified a relative recurrence risk of 48, one of the highest among all types of CHD. This suggests that common and rare variants may contribute to risk of non-Mendelian vPS. To address these important gaps in knowledge about Mendelian and complex genetic (non-Mendelian) etiologies of vPS, we will analyze genome sequencing from our own Gabriella Miller Kids First cohort, which includes over 500 individuals with vPS. Our analysis of this data set will 1) Identify rare and novel Mendelian etiologies of vPS and 2) Define the genetic etiology of non-Mendelian vPS. Results of our study will inform genetic testing recommendations for infants and children with vPS. Earlier diagnosis of genetic disorders and understanding how genetic variants contribute to pathogenesis and ultimately outcomes of vPS can improve health and developmental outcomes by allowing anticipatory rather than reactionary guidance and management. Ultimately, the goal of this study is to advance the use of genomic information as part of routine care for individuals with vPS in order to provide early and accurate anticipatory guidance to families and healthcare teams.

摘要 先天性心脏病（CHD）是最常见的一类出生缺陷，每100例活产婴儿中就有1例发生， 已知具有孟德尔和复杂的遗传病因学。有多项研究调查了遗传 对特定类型CHD的贡献，但右心室流出道病变缺失或代表性不足 在这样的研究中。瓣膜性肺动脉狭窄（vPS）是一种右心室流出道梗阻， 约10%的CHD。四分之一的vPS患者需要球囊瓣膜成形术和/或 心内直视手术修复，其中一部分需要对复发性瓣膜狭窄进行重复干预，或 修复瓣膜关闭不全/返流。因此，vPS的诊断代表了重要的终身医疗保健 负担我们的单中心回顾性研究表明，204例vPS先证者中有10%携带遗传性 诊断，但只有18%的队列接受了遗传评价和/或检测（安德森等人，2019）。在 相比之下，我们对123例测序的vPS先证者（外显子组或基因组）进行了未发表的分析， 孟德尔诊断占17%。努南综合征是一种常染色体显性遗传的疾病， 这是两个队列中最常见的诊断。在两组中， 心脏外和/或神经发育异常的儿童没有基因诊断。总之，这是 高度提示孟德尔诊断在vPS患者中被低估， 是新的致病基因尚未确定。此外，对右心室流出道的家族性复发的研究 阻塞性CHD的相对复发风险为48，是所有类型CHD中最高的。这 表明常见和罕见变异可能导致非孟德尔vPS的风险。解决这些 关于vPS的孟德尔和复杂遗传（非孟德尔）病因学知识的重要空白，我们将 分析来自我们自己的加布里埃拉米勒儿童第一队列的基因组测序，其中包括500多个个体 vPS的。我们对该数据集的分析将1）确定vPS的罕见和新型孟德尔病因学，2）定义 非孟德尔vPS的遗传病因学我们的研究结果将为遗传检测提供建议， vPS的婴儿和儿童。遗传疾病的早期诊断和了解遗传变异如何 有助于发病机制和最终结果的vPS可以改善健康和发展的结果， 允许预期的而不是反动的指导和管理。最终，本研究的目标是 推进基因组信息的使用，作为vPS患者常规护理的一部分，以便提供早期 并为家庭和医疗团队提供准确的预期指导。