Congenital Heart Disease Expert Curation Panel

先天性心脏病专家治疗小组

• 批准号: 10413445
• 负责人: BRUCE D GELB
• 金额: $ 41.34万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413445
• 关键词: Address; Affect; Animal Model; Attention; Benign; Biological Assay; Birth; Boston; Candidate Disease Gene; Cardiac; Cardiac development; Cardiovascular Diseases; Cardiovascular system; Cells; Classification; ClinVar; Clinical; Collaborations; Communication; Communities; Complex; Congenital Abnormality; Congenital Heart Defects; Data; Development; Diagnosis; Diagnostic; Disease; Epidemiology; Funding; Genes; Genetic; Genetic Research; Genetic Variation; Genome; Genotype; Goals; Heart Abnormalities; Heritability; Human Genetics; Individual; Infant; Institutes; Intellectual functioning disability; International; Laboratories; Medical Genetics; Mentors; Modeling; Mutation; Newborn Infant; Outcome; Participant; Pathogenesis; Pathogenicity; Patients; Pediatric Cardiac Genomics Consortium; Phenotype; Procedures; Research; Review Literature; Risk; Role; Science; Single Nucleotide Polymorphism; Structural defect; Syndrome; Testing; Training; United States National Institutes of Health; Variant; Work; autism spectrum disorder; base; bicuspid aortic valve; biochemical model; cardiogenesis; clinical care; clinically relevant; clinically significant; comorbidity; congenital heart disorder; exome sequencing; experience; genetic architecture; genetic panel test; genetic testing; genetic variant; genome-wide; insertion/deletion mutation; interest; member; next generation sequencing; novel; outreach; research clinical testing; trait

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.

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， 出生时就存在，是最常见的出生缺陷，当二尖瓣主动脉瓣畸形时，影响 2-3% 的新生儿 包括。虽然早在 1800 年代中期就被认为是一种潜在的遗传性状，但 支持先天性心脏病主要是遗传性这一观点的流行病学证据才刚刚出现 在过去的35年里。迄今为止，已经确定了 253 个与 CHD 相关的基因，但数量要少得多。 使用正式的 ClinGen 基因管理已将基因指定为导致 CHD 的基因。此外，还有 个体变异的临床相关差异（即致病性/可能致病性与良性/可能致病性） 良性）存在于大量此类基因中。使用CHD基因进行基于测序的临床基因检测 小组有助于对存在可采取行动的合并症进行诊断，而这些合并症往往会出现其他情况 未被发现，特别是在年幼的婴儿中，他们的综合征特征可能尚未明显但可用 商业冠心病基因检测组的基因含量差异很大。拟议的 CHD ECP 将 汇集了来自世界各地的 CHD 基因专家，组织良好，符合 ClinGen 标准 方式，将整理基因-CHD 对并对它们的变异进行分类。 MPI 和许多专家策展 小组成员在 NIH 支持的长期联盟（儿科 心脏基因组联盟）已经并将继续阐明心脏性状的遗传结构 兴趣（CHD）从而带来重要的基因和变异管理经验。将重点关注 借鉴广泛的科学知识，为特定的先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）。这项努力恰逢其时，因为 可用于临床基因检测的潜在基因正在迅速增加，此类检测的临床效用良好 已确立的。此外，候选冠心病基因具有令人信服的人类遗传致病性证据，但 可以与心脏发育研究界共享的功能数据很少，以供考虑。这 CHD ECP 将填补临床护理的重要空白。