Genetics of SCID

Abstract

Human SCID (Severe Combined Immunodeficiency) is a prenatal disorder of T lymphocyte development, that depends on the expression of numerous genes. The knowledge of the genetic basis of SCID is essential for diagnosis (e.g., clinical phenotype, lymphocyte profile) and treatment (e.g., use and type of pre-hematopoietic stem cell transplant conditioning).Over the last years novel genetic defects causing SCID have been discovered, and the molecular and immunological mechanisms of SCID have been better characterized. Distinct forms of SCID show both common and peculiar (e.g., absence or presence of nonimmunological features) aspects, and they are currently classified into six groups according to prevalent pathophysiological mechanisms: impaired cytokine-mediated signaling; pre-T cell receptor defects; increased lymphocyte apoptosis; defects in thymus embryogenesis; impaired calcium flux; other mechanisms.This review is the updated, extended and largely modified translation of the article "Cossu F: Le basi genetiche delle SCID", originally published in Italian language in the journal "Prospettive in Pediatria" 2009, 156:228-238.

Figure 1

T cell Receptor Excision Circles (TRECs). TRECs are episomal DNA circles produced in thymocytes by excisional rearrangements of T cell receptor (TCR) genes; they are stable, not duplicated during mitosis, diluted out with each cell division, and therefore higher in thymocytes, recent thymic emigrants (RTEs) and naïve T cells. Quantitative polymerase chain reaction (PCR) of coding-joint (cj) δRec ψJα TREC, produced at TCRα/δ locus within chromosome 14 (14q11) by > 70% of developing human α:β T cells, counts in the peripheral blood naïve α:β T lymphocytes recently dismetted by thymus: in newborn, values < 25 TRECs/μL indicate SCID.

Figure 2

Wisconsin Newborn SCID screening poster. Reproduced with kind permission of the WI State Laboratory of Hygiene, http://www.slh.wisc.edu/posters/Baker102808.pdf.

Figure 3

Monoclonal IgG gammopathy in a Sardinian 4-month-old female infant. AR T^-B^-NK⁺SCID, modified to T⁺⁺B^-NK⁺ SCID by massive maternal T lymphocyte engraftment; ALC 16,740/μL, IgG 3,390 mg/dL; homozygous frameshift > nonsense mutation of DCLRE1C gene (Artemis defect).

Figure 4

Omenn Syndrome in a Sardinian 5-month-old female infant (absence of RAG1-RAG2 mutations, unidentified gene defect). "Leaky" mutations of practically all SCID genes (whose null mutations cause instead typical SCID) produce Omenn syndrome, in fact described in infants with defects of RAG1-RAG2, DCLRE1C-Artemis, ADA, DNA Ligasi IV, RMRP-CHH, common γc, IL7Rα, WHN-FOXN1, ZAP-70, and complete DiGeorge anomaly (DiGeorge Syndrome; CHARGE). In many infants with Omenn syndrome, that is clinically not leaky but very serious, genetic defect remains unidentified (several known, and probably also unknown, genes to be sequenced).

Figure 5

David Vetter, the "Bubble Boy" (September 21, 1971 - February 22, 1984). David Vetter, photograph reproduced with kind permission of Prof. William T. Shearer, The David Center, Baylor College of Medicine, Texas Children's Hospital.

Figure 6

Pediatric Research 1977, January. In January 1977, a special issue of Pediatric Research (cover) reported about David Vetter.

Figure 7

Pre-TCR and pre-BCR. Schematic drawing of pre-T cell receptor (pre-TCR; thymus, large pre-T cell with rearranged TCRβ gene) and pre-B cell receptor (pre-BCR; bone marrow, large pre-B cell with rearranged IgHμ gene). Defects of the pre-TCR, subdivided into defects of V(D)J recombination and defects of signaling through the pre-T cell receptor, cause arrest of the development of T lymphocytes at the stage of large pre-T cell and therefore SCID; defects of the pre-BCR cause arrest of the development of B lymphocytes at the stage of large pre-B cell and therefore agammaglobulinemia.

Figure 8

Hoyeraal-Hreidarsson Syndrome. Cerebellar hypoplasia in a Sardinian 6-month-old male with T⁺B^-NK^- SCID; missense mutation of DKC1 gene encoding dyskerin (X-linked Hoyeraal-Hreidarsson syndrome).