Clinical Domain Working Groups

Severe Combined Immune Deficiency (SCID) represents one of the most severe inborn errors of immunity (IEI). The term “combined” indicates that patients with these disorders have defects in both T cell and B cell function, making them susceptible to life-threatening viral, fungal, and bacterial infections.

The IUIS IEI Committee was originally created under the auspices of the World Health Organization in 1973 to describe and classify the types of primary immune defects (PIDDs) affecting humans. The committee is tasked with maintaining a list of immunologic disorders. Since the 1970s, it has maintained a curated list to ensure a standard nomenclature and consistent approach. After discovery of the first genetic defects associated with PIDD, the committee has also maintained a list of genes that have been associated with IEI in peer-reviewed published reports. This list is updated approximately every 3 years and published online and in print. The most recent update was performed in 2019 and published in January 2020. It lists 430 genes that have been associated with IEI in peer-reviewed publications. These 430 genes are divided across 10 tables based on their associations with various clinical immunodeficiency phenotypes.

This VCEP will focus on the genes associated with a SCID phenotype included in Table 1 of the IUIS document, which encompasses 18 genes: IL2RG, JAK3, IL7R, PTPRC, CD3D, CD3E, CD247, CORO1A, LAT, RAG1, RAG2, DCLRE1C, PRKDC, NHEJ1, LIG4, ADA, AK2, and RAC2,  as well as  FOXN1.  Variants in RMRP will also be curated because RMRP deficiency stands as the 6^th most common molecular cause of abnormal newborn screening tests for SCID in the United States. The SCID VCEP will first work on specifying the ACMG variant curation guidelines for 8 of these 18 genes, including: IL2RG, RAG1, IL7R, ADA, JAK3, DCLRE1C, RAG2, RMRP  and  FOXN1.