Curation of genetic defects causing combined immunodeficiency and infections in children

摘要 400多个基因的缺陷现在被认为与原发性免疫缺陷疾病的发生有关 (PIDD)。最严重的疾病称为联合免疫缺陷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)间隔的缺陷 对免疫系统的影响。因此，他们在生命早期和早产时极易受到感染。 如果不积极使用抗菌药、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点进行筛查(NBS)。由于特定的基因缺陷存在于 患有SCID的患者具有可操作的后果(即，决定可能 推荐)，国家统计局确认的患者通常会使用基因面板或外显子组进行早期基因测试 测序。通常，基因检测会返回一个或多个“不确定意义的变种”的结果 一个以前与SCID或CID表型无关的基因的变异(S)。提供者和家庭是 因此，留下来尝试和收集证据来确定特定基因或变种的致病性。这一努力 可能会延误护理或导致不太理想的治疗选择。因此，对专家的迫切需求存在 治疗导致SCID和CID的遗传缺陷。此应用程序的目标是管理 将特定基因与SCID或CID表型联系起来的证据以及所有变异致病的证据 在国家统计局确定的与婴儿SCID相关的8个最常见基因中。这个目标将是 完成的具体目标有两个：1)建立一个基因治疗专家小组(GCEP)来主持 有证据表明，已报告的导致SCID或CID的基因与临床疾病的发展有关 Clingen标准，以及2)建立一个不同的诉讼专家小组(VCEP)，以管理证据 基于患病率的8个最常见的SCID相关基因中报告的所有变异的致病性 在国家统计局确认的婴儿中。由于免疫细胞可以很容易地从体内移除，以实现 通过测试，基础免疫学研究中存在大量已发表的数据，这些数据可能为这项工作提供信息。这 因此，该提案是创新的，因为它将提供资源，允许GCEP和VCEP小组将这一点联系起来 丰富的已发表的分子和功能免疫学数据以及已发表的临床和基因数据 案例和公共数据库。这项工作意义重大，并将立即产生积极影响，因为 整理关于基因和基因变异致病性的证据并将其公之于众 影响如上所述及时选择治疗的可立即采取行动的后果。建议数 因此，研究解决了NIH和本RFA的任务，重点是建立专家 分析对临床实践有较大影响的相关遗传和功能数据的专家小组，以减少 减少疾病和残疾的负担，改善遗传易受感染儿童的生活。

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.