Curation of genetic defects causing combined immunodeficiency and infections in children

摘要 超过400个基因的缺陷现在已经与原发性免疫缺陷疾病的发展有关 （PIDD）.最严重的疾病被称为联合或严重联合免疫缺陷（CID或SAFE）。 SCID），因为它们导致细胞（T细胞）和体液（B细胞）区室缺陷的组合 免疫系统。因此，它们导致在生命早期对感染的高度易感性， 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，现在大多数SCID患者都是通过新生儿 在出生时获得的干血斑上进行的NBS筛查。由于特定的基因缺陷存在于 患有SCID的患者具有可采取行动的后果（即，决定了积极治疗的类型， 推荐），NBS确定的患者通常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”的结果， 先前与SCID或CID表型无关的基因中的变异。供应商和家庭 因此，留给他们的是试图收集证据来确定特定基因或变体的致病性。这一努力 可能会延误治疗或导致治疗选择不佳。因此，迫切需要专家 治疗导致SCID和CID的遗传缺陷。此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体致病性的证据 在NBS确定的婴儿中与SCID相关的8个最常见的基因中。这一目标将 完成了两个具体目标：1）建立基因策展专家小组（GCEP）， 将报告的引起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）建立变异型治疗专家小组（VCEP），以收集以下方面的证据： 根据患病率，8种最常见的SCID相关基因中报告的所有变体的致病性 在国家统计局确定的婴儿中。由于免疫细胞可以很容易地从身体中取出， 测试，丰富的出版数据存在从基础免疫学研究，可以告知这项工作。这 因此，该提案具有创新性，因为它将提供资源，使GCEP和VCEP小组能够将这一点联系起来， 丰富的已发表的分子和功能免疫学数据，以及来自已发表的 案例和公共数据库。这项工作意义重大，将立即产生积极影响，因为 收集有关基因和基因变异的致病性的证据并将其公开， 影响如上所述的及时治疗选择的立即可采取行动的后果。拟议 因此，研究通过集中于建立专家小组来解决NIH和RFA的使命问题。 分析对临床实践有高度影响的相关遗传和功能数据的小组， 减轻疾病和残疾负担，改善遗传易感性儿童的生活。

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.