Curation of genetic defects causing combined immunodeficiency and infections in children

治疗导致儿童联合免疫缺陷和感染的遗传缺陷

• 批准号: 10435461
• 负责人: Ivan Kingyue Chinn
• 金额: $ 35.1万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435461
• 关键词: Address; Affect; Age; Antibody Response; B-Lymphocytes; Birth; Blood; Bone Marrow Transplantation; Caring; Cell Compartmentation; Cells; Cessation of life; Child; ClinVar; Data; Databases; Defect; Development; Diagnosis; Disease; Ensure; Family; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Goals; Guidelines; Hereditary Disease; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunologics; Immunology; Incidence; Individual; Infant; Infection; International; Lead; Left; Life; Link; Live Birth; Medical Genetics; Mission; Molecular; Mutation; Neonatal Screening; Newborn Infant; Outcome; Pathogenicity; Patient Care; Patients; Peer Review; Phenotype; Predisposition; Prevalence; Procedures; Provider; Publishing; Reporting; Research; Resources; Review Literature; Severe Combined Immunodeficiency; Societies; Spottings; T-Lymphocyte; Testing; Time; Transplantation Conditioning; United States; United States National Institutes of Health; Vaccines; Variant; Wisconsin; Work; aggressive therapy; antimicrobial; base; burden of illness; clinical development; clinical practice; congenital immunodeficiency; disability; early childhood; enzyme replacement therapy; evidence base; exome sequencing; gene panel; gene therapy; genetic testing; genetic variant; hematopoietic cell transplantation; improved; infancy; innovation; opportunistic pathogen; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; premature; prevent; programs; public database; recurrent infection; screening; success; transplantation therapy; tv watching; variant of unknown significance; virtual; web site

ABSTRACT Defects in over 400 genes have now been linked to the development of primary immunodeficiency disorders (PIDD). The most severe disorders are known as Combined or Severe Combined Immune Deficiencies (CID or SCID) because they cause a combination of defects in both cellular (T-cell) and humoral (B-cell) compartments of the immune system. As a result, they lead to profound susceptibility to infections early in life and premature death if not treated aggressively with antimicrobials, hematopoietic cell transplant (HCT), gene therapy (GT), or enzyme replacement therapy (ERT). In the U.S., most patients with SCID are now identified by newborn screening (NBS) performed on dried blood spots obtained at birth. Since the specific gene defect present in a patient with SCID has actionable consequences (i.e., dictates the type of aggressive therapy that may be recommended), patients identified by NBS typically undergo early genetic testing using gene panels or exome sequencing. Frequently, genetic testing returns a result of one or more “Variants of Uncertain Significance” or variant(s) in a gene not previously associated with a SCID or CID phenotype. Providers and families are therefore left to try and gather evidence to determine pathogenicity of a particular gene or variant. This effort may delay care or lead to a less-than-optimal choice of therapy. A critical need therefore exists for expert curation of the genetic defects that result in SCID and CID. The objective of this application is to curate the evidence linking specific genes to a SCID or CID phenotype and the evidence for pathogenicity of all variants in the 8 most prevalent genes associated with SCID in infants identified by NBS. This goal will be accomplished with 2 specific aims: 1) Establishment of a Gene Curation Expert Panel (GCEP) to curate evidence linking genes reported to cause SCID or CID to the development of clinical disease according to ClinGen criteria, and 2) Establishment of a Variant Curation Expert Panel (VCEP) to curate evidence for pathogenicity of all variants reported in the 8 most common SCID-associated genes based upon prevalence among infants identified by NBS. Since immune cells can be readily removed from the body for functional testing, a wealth of published data exists from basic immunology studies that may inform this work. This proposal is therefore innovative because it will provide resources to allow GCEP and VCEP panels to link this wealth of published molecular and functional immunology data with clinical and genetic data from published cases and public databases. The work is significant and will have an immediate positive impact because curating evidence about the pathogenicity of genes and gene variants and making it publicly available has immediate actionable consequences that affect timely choice of therapy as described above. The proposed research therefore addresses the mission of the NIH and this RFA by focusing on the establishment of Expert Panels to analyze relevant genetic and functional data with high impact on clinical practice to reduce the burden of illness and disability and improve the lives of children with genetic susceptibility to infection.

抽象的 目前已发现 400 多个基因的缺陷与原发性免疫缺陷病的发生有关 （PIDD）。最严重的疾病被称为联合或严重联合免疫缺陷（CID 或 SCID），因为它们会导致细胞（T 细胞）和体液（B 细胞）区室的缺陷组合 免疫系统的。因此，它们导致生命早期和早产儿对感染的高度敏感。 如果不积极使用抗菌药物、造血细胞移植 (HCT)、基因治疗 (GT) 或 酶替代疗法（ERT）。在美国，大多数 SCID 患者现在都是通过新生儿来识别的 对出生时获得的干血斑进行筛查（NBS）。由于特定的基因缺陷存在于 SCID 患者具有可采取行动的后果（即，决定了可能采取的积极治疗类型） 建议），国家统计局发现的患者通常会使用基因组或外显子组进行早期基因检测 测序。通常，基因检测会返回一个或多个“不确定意义的变异”或 先前与 SCID 或 CID 表型无关的基因变异。提供者和家庭是 因此，我们需要尝试收集证据来确定特定基因或变异的致病性。这个努力 可能会延误护理或导致治疗选择不太理想。因此迫切需要专家 治疗导致 SCID 和 CID 的遗传缺陷。该应用程序的目的是策划 将特定基因与 SCID 或 CID 表型联系起来的证据以及所有变异的致病性证据 NBS 确定的与婴儿 SCID 相关的 8 个最常见基因。这个目标将是 完成了两个具体目标：1）建立基因管理专家小组（GCEP）来管理 根据报告，将导致 SCID 或 CID 的基因与临床疾病的发展联系起来的证据 ClinGen 标准，以及 2) 建立变体管理专家小组 (VCEP) 来管理证据 根据患病率，8 个最常见 SCID 相关基因中报告的所有变异的致病性 国家统计局认定的婴儿中。由于免疫细胞可以很容易地从体内去除以发挥功能 测试中，基础免疫学研究中存在大量已发表的数据，可以为这项工作提供信息。这 因此，该提案具有创新性，因为它将提供资源，让 GCEP 和 VCEP 小组将这一点联系起来 大量已发表的分子和功能免疫学数据以及已发表的临床和遗传数据 案例和公共数据库。这项工作意义重大，并将产生立竿见影的积极影响，因为 整理有关基因和基因变异致病性的证据并将其公开 如上所述，影响及时选择治疗的直接可采取行动的后果。拟议的 因此，研究通过重点建立专家来解决 NIH 和本 RFA 的使命。 小组分析对临床实践具有重大影响的相关遗传和功能数据，以减少 疾病和残疾负担并改善具有感染遗传易感性的儿童的生活。