Curation of genetic defects causing combined immunodeficiency and infections in children

Defects in almost 500 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., all 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 can 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 expand curation of the pathogenicity of variants in SCID-associated genes and curation of the evidence linking specific genes to SCID or CID. This goal will be accomplished with 4 specific aims: 1) Curation of the evidence for pathogenicity of new variants reported in the 7 most common SCID-associated genes based on prevalence among infants identified by NBS screening; 2) Determination of the evidence for pathogenicity of RMRP variants; 3) Curation of the evidence for pathogenicity of variants in the 2 next most prevalent SCID-associated genes (CD3D and LIG4), and 4) Curation of the evidence linking new genes reported to cause SCID or CID to the development of disease. This proposal is innovative because these efforts constitute ground-breaking endeavors to establish and apply validated ACMG-based rules for variant classification in the clinical realm of SCID, and the work with RMRP stands as a pioneering landmark undertaking in the field of clinical genetics because ACMG guidelines have never been adapted for a non-protein encoding gene like RMRP before. 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 advancement of Expert Panels to analyze relevant genetic and functional data with high impact on clinical practice to reduce the burden of illness and impairments and improve the lives of children with genetic susceptibility to infection.