Congenital Heart Disease Expert Curation Panel

ClinGen CHD ECP项目摘要摘要 先天性心脏缺陷（CHD），定义为心脏和大血管的结构畸形， 在出生时就存在，是最常见的出生缺陷，当二叶式主动脉瓣植入时， 包括.虽然早在19世纪中期就被认为是一种潜在的遗传特征，但确定的 流行病学证据支持CHD主要是遗传性的观点， 在过去的35年里。到目前为止，已经确定了253个导致CHD的基因，但数量要少得多。 使用正式的ClinGen基因管理，已将基因指定为CHD致病基因。此外，还有 个体变体的临床相关差异（即，致病性/可能致病性vs.良性/可能 良性）在这些基因的大量。基于测序的CHD基因临床基因检测 面板有助于诊断，其中有可采取行动的合并症，往往会去，否则 未被发现，尤其是在幼儿中，其综合征特征可能尚不明显，但可用 商业CHD基因检测面板在其基因含量上差异很大。拟议的CHD ECP将 汇集了来自世界各地的CHD基因专家，以组织严密、符合ClinGen的方式 方式，将策划基因CHD对和分类他们的变种。MPI的和许多专家策展 专家组成员在NIH支持的长期联盟（儿科）上进行了广泛的合作 心脏基因组联盟），并继续阐明遗传结构的特点， 兴趣（CHD），从而带来了重要的基因和变异的治疗经验。重点将放在 为给定的CHD特征制定实验证据标准，从广泛的科学领域中汲取经验， （心脏发育的生物化学、细胞和动物模型）。这一努力的时机很好， 可用于临床基因检测的潜在基因正在迅速增加， 确立了习此外，候选CHD基因具有令人信服的人类致病性遗传证据，但 可以与心脏发育研究团体共享不足的功能数据以供考虑。的 CHD ECP将填补临床护理的重要空白。

ClinGen CHD ECP Project Summary Abstract Congenital heart defects (CHD), defined as structural malformations of the heart and great vessels that are present at birth, are the commonest birth defects, affecting 2-3% of newborns when bicuspid aortic valve is included. While understood to be potentially a heritable trait as early as the mid-1800s, definitive epidemiological evidence supporting the notion that CHD was primarily genetic in its origins has only emerged in the last 35 years. To date, 253 genes contributing to CHD have been established but a far smaller number of genes have been designated as CHD-causing using formal ClinGen gene curation. Furthermore, and there are clinically relevant discrepancies for individual variants (i.e., pathogenic/likely pathogenic vs. benign/likely benign) in a substantial number of these genes. Sequencing-based clinical genetic testing using CHD gene panels facilitates diagnoses for which there are actionable co-morbidities that would often go otherwise undetected, particularly in young infants in whom syndromic features may not yet be evident but available commercial CHD genetic testing panels vary substantially in their gene content. The proposed CHD ECP will bring together experts in CHD genes from around the world which, in a well-organized, ClinGen-compliant manner, will curate gene-CHD pairs and classify their variants. The MPI's and many of the Expert Curation Panel members have extensive prior collaboration on a long-standing NIH-supported consortium (Pediatric Cardiac Genomic Consortium) that has and continues to elucidate the genetic architecture of the trait of interest (CHD) thus bringing significant gene and variant curation experience. An emphasis will be placed on developing experimental evidence criteria for a given CHD trait, drawing from a notably broad range of science (biochemical, cell-based, and animal models of heart development). This effort is well timed as the numbers of potential genes available for clinical genetic testing is rising rapidly and the clinical utility of such testing is well established. Further, candidate CHD genes with compelling human genetic evidence for pathogenicity but scant functional data can be shared with the cardiac developmental research community for consideration. The CHD ECP will fill an important gap in clinical care.