Genetics of severe combined immunodeficiency

Abstract

Severe Combined Immunodeficiency (SCID) is an inherited group of rare, life-threatening disorders due to the defect in T cell development and function. Clinical manifestations are characterised by recurrent and severe bacterial, viral, and fungal opportunistic infections that start from early infancy period. Haematopoietic stem cell transplantation (HSCT) is the treatment of choice. The pattern of inheritance of SCID may be X-linked or autosomal recessive. Though the diagnosis of SCID is usually established by flow cytometry-based tests, genetic diagnosis is often needed for genetic counselling, prognostication, and modification of pre-transplant chemotherapeutic agents. This review aims to highlight the genetic aspects of SCID.

Keywords: Adenosine deaminase; Flow cytometry; Genetics; Newborn screening; Severe combined immunodeficiency.

Figure 1

Phenotypic classification of severe combined immunodeficiency (SCID).

Figure 2

Schematic representation of SCID genes and their associated domains. (A)RAG1 gene showing core region domains as nonamer binding domain (NBD), a central domain and the C′ terminal domain. The non-core region have zinc dimerization domain (ZDD) having zinc finger A (ZFA), central non-core domain (CND). The three active site residues are shown by D600, D708 and E649. (B)RAG2 gene showing the 6-bladed beta-propeller structure in the N terminal core region. The non-core region shows acidic hinge region and plant homeodomain (PHD). (C)DCLRE1C gene (Artemis) showing three distinct regions belonging to Metallo-β−lactamase superfamily namely β-lactamase domain, β- CASP domain and C′ terminal domain. (D)PRKDC gene showing 5′ DNA interacting site, leucine-rich repeats, phosphorylation cluster. sites (PQR, ABCDE), helix-turn-helix repeats while FAT, FATC, PI3K kinase domains and caspase 3 cleavage site are present at C-terminal region. (E)IL2RG gene showing Interleukin-6 receptor alpha binding domain (IL6Ra-bind), fibronectin III binding domain (FN3), the WSXWS motif, transmembrane domain (TM), and Box 1 domain.