Congenital Heart Disease Expert Curation Panel

Clingen CHD ECP项目摘要 先天性心脏病(CHD)，定义为心脏和大血管的结构性畸形， 是最常见的出生缺陷，影响2-3%的新生儿，当二尖瓣主动脉瓣 包括在内。虽然早在19世纪中期就被认为是一种潜在的可遗传特征，但最终的 支持冠心病起源主要是遗传的流行病学证据才刚刚出现。 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基因管理已被指定为导致CHD的基因。此外，还有 个别变异的临床相关差异(即致病/可能致病与良性/可能 良性)存在于大量这些基因中。利用CHD基因进行基于测序的临床基因检测 Panels有助于诊断存在可操作的并存疾病，否则通常会出现这种情况 未被发现，特别是在婴儿中，他们的症状特征可能还不明显，但可以得到 商业CHD基因检测小组的基因含量差异很大。拟议的CHD ECP将 将来自世界各地的CHD基因专家聚集在一起，在一个组织严密、符合克林根的 将整理基因-CHD对并对它们的变种进行分类。MPI和许多专家大会 专家小组成员在NIH支持的长期财团(儿科)上有广泛的先前合作 心脏基因组联合会)，它已经并继续阐明心脏疾病特征的遗传结构 因此，兴趣(CHD)带来了显著的基因和变异的治疗经验。重点将放在 从非常广泛的科学领域为特定的冠心病特征制定实验证据标准 (心脏发育的生化、细胞和动物模型)。这一努力来得正是时候，因为 可用于临床基因检测的潜在基因正在迅速增加，这种检测的临床实用性很好。 已经成立了。此外，具有令人信服的人类致病性遗传证据的候选CHD基因 很少有功能数据可以与心脏发育研究界共享以供考虑。这个 CHD ECP将填补临床护理的一个重要空白。

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.