Gene Curation Expert Panel for Syndromic Disorders

摘要 在影响儿科疾病的罕见遗传疾病中，综合症占很大比例 人口，包括许多具有结构性出生缺陷和其他先天畸形的疾病。这些 疾病是导致发病率和死亡率的不成比例的原因。准确的分子诊断对于 医疗管理、计划生育和从事研究工作。下一代测序具有 推动了发现新的遗传综合症的步伐，但在 基因-疾病关系(GDR)的证据使基因检测的应用复杂化。我们有 成立了国际疾病组--综合症基因治疗专家组(SD-GCEP 代表五大洲23个机构的专家、基因管理框架专家和生物策略师 彻底精选支持致病基因关系的证据，并量化 使用临床基因组资源(Clingen)开发的框架来加强这一证据。可持续发展署- GCEP由来自主要利益攸关方的代表组成，包括在线孟德尔人遗传 (OMIM)、Monch Initiative的Mondo疾病本体论、基因组学英国PanelApp、PanelApp Australia、 孟德尔基因组学中心，诊断实验室(Ambry，Illumina，Invitae)，临床实践 遗传学家、遗传咨询师、罕见病和模型生物体研究人员。在目标1中，我们将执行68 代表最常见测试的综合症障碍的GDR先兆、治疗和复发不是 在其他GCEP的范围内，通常集中在特定的器官或途径上。在目标2中，我们将 对通过临床表型和治疗确定的症状性GDR进行89次先兆、治疗和复发 由诊断实验室与参与SD-GCEP的人员一起执行的基因组测序。在目标3A中， 我们将对新发现的综合症GDR执行24次预报、精准和递归 孟德尔基因组学中心，因为诊断实验室对这些中心高度感兴趣，以确定 应该将基因添加到专家小组和临床医生中，以指导临床诊断和管理。SD-GCEP 具有丰富的经验和协作性。在AIM 3B中，我们将继续接受其他GCEP的请求，以 对其他GCEP范围之外的15个感兴趣的GDR进行管理，原因是 条件。总共，我们将为综合症障碍进行196次GDR的前驱、治疗和递归 三年多了。所有的策展都将使用Clingen基因修复界面进行并公开共享 通过Clingen知识库改进对综合症疾病的基因检测和诊断，并 强调需要进一步研究的地方。

ABSTRACT Syndromic disorders account for a large proportion of the rare genetic disorders that impact the pediatric population, including many conditions with structural birth defects and other congenital anomalies. These conditions are a disproportionate cause of morbidity and mortality. Accurate molecular diagnosis is important for medical management, family planning, and engagement in research studies. Next generation sequencing has driven the pace of discovery of novel genetic syndromes, yet there are marked inconsistencies in the level of evidence for gene-disease relationships (GDRs) that complicate the application of genetic testing. We have formed the Syndromic Disorders Gene Curation Expert Panel (SD-GCEP), an international group of disease experts, gene curation framework experts, and biocurators representing 23 institutions across 5 continents to thoroughly curate the evidence supporting the relationship of a gene in causing a disease, and to quantify the strength of that evidence using the framework developed by the Clinical Genome Resource (ClinGen). The SD- GCEP consists of representatives from major stakeholders including Online Mendelian Inheritance in Man (OMIM), Monarch Initiative’s Mondo disease ontology, Genomics England PanelApp, PanelApp Australia, Centers for Mendelian Genomics, diagnostic laboratories (Ambry, Illumina, Invitae), practicing clinical geneticists, genetic counselors, and rare disease and model organism researchers. In Aim 1, we will perform 68 GDR precurations, curations and recurations representing the most commonly tested syndromic disorders not within the purview of other GCEPs, which generally focus on a specific organ or pathway. In Aim 2, we will perform 89 precurations, curations, and recurations for syndromic GDRs identified through clinical exome and genome sequencing performed by diagnostic laboratories with personnel involved in the SD-GCEP. In Aim 3A, we will perform 24 precurations, curations, and recurations for newly discovered syndromic GDRs from the Centers for Mendelian Genomics, as these are of high interest to diagnostic laboratories to determine when genes should be added to panels and to clinicians to guide clinical diagnosis and management. The SD-GCEP is highly experienced and collaborative. In Aim 3B, we will continue to accept requests from other GCEPs to curate 15 GDRs of interest that are beyond the scope of the other GCEP due to the syndromic nature of the condition. In total, we will perform 196 precurations, curations, and recurations of GDRs for syndromic disorders over three years. All curations will be performed using the ClinGen Gene Curation Interface and publicly shared though the ClinGen knowledgebase to improve genetic testing and diagnosis for syndromic disorders and to highlight where further research is needed.