Gene Curation Expert Panel for Syndromic Disorders

摘要 综合征性疾病占影响儿科患者的罕见遗传性疾病的很大比例。 这是一个非常普遍的问题，包括许多结构性出生缺陷和其他先天性异常。这些 条件是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。下一代测序技术 推动了发现新的遗传综合征的步伐，然而， 基因-疾病关系（GDR）的证据使基因检测的应用复杂化。我们有 成立了综合征性疾病基因治疗专家小组（SD-GCEP），这是一个国际疾病组织， 专家，基因策展框架专家和代表五大洲23个机构的生物学家， 彻底策划证据支持的关系，基因在导致疾病，并量化 使用临床基因组资源（ClinGen）开发的框架来增强证据。SD- GCEP由来自主要利益相关者的代表组成，包括在线人类孟德尔遗传 （OMIM），Monarch Initiative的Mondo疾病本体，Genomics England 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，罕见疾病和模式生物研究人员。在目标1中，我们将执行68 代表最常检测的综合征性疾病的GDR缓解、治愈和复发， 在其他GCEP的范围内，这些GCEP通常侧重于特定的器官或途径。在目标2中，我们将 对通过临床外显子组鉴定的综合征性GDR进行了89次简化、治疗和复发， 由诊断实验室与参与SD-GCEP的人员进行基因组测序。在Aim 3A中， 我们将对新发现的综合征性GDR进行24次解释、治疗和递归， 孟德尔基因组学中心，因为这些是高度感兴趣的诊断实验室，以确定何时 基因应被添加到面板和临床医生，以指导临床诊断和管理。关于SD-GCEP 经验丰富，善于合作在目的3B方面，我们会继续接受其他GCEPs的要求， 策划15个感兴趣的GDR，这些GDR由于其综合征性质而超出了其他GCEP的范围。 条件我们总共将对196例综合征性疾病进行GDR的诊断、治疗和复发 超过三年。所有治疗将使用ClinGen基因治疗界面进行，并公开共享 通过ClinGen知识库，改善综合征性疾病的基因检测和诊断， 强调需要进一步研究地方。

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.