Severe Combined Immune Deficiency (SCID): Genetics


Severe combined immunodeficiency consists of an array of genetically determined blocks in T‐lymphocyte development. Characterisation of genetic defects contributes to a better understanding of lymphocyte differentiation pathways. Seventeen distinct defects have now been characterised that affect multiple steps of T lymphocytes ontogenesis, from defective survival of several haematopoietic lineage precursors, premature cell death of lymphocyte precursors, defective interleukin‐7‐dependent survival/proliferation of T‐lymphocyte precursors, defective recombination of T‐cell receptor (TCR) genes, defective (pre) TCR signalling and defective egress of the thymus. These disorders are life threatening because of the early onset of various infections notably caused by opportunistic agents, hence stressing the importance of T cell adaptive immunity in longevity. These disorders can be cured by allogeneic haematopoietic stem cell transplantation, some by gene therapy while neonatal screening is being developed.

Key Concepts:

  • Severe combined immunodeficiencies are rare inherited diseases caused by defective development of the T lymphocyte lineage.

  • Clinical consequences are devastating leading to death within the first year of life in the absence of treatment.

  • Allogeneic transplantation of haematopoietic stem cells or in some cases gene therapy can be life saving by restoring T‐cell development.

  • Seventeen different genetic defects have been found to cause SCID, they are classed in six groups as based on pathophysiology.

  • SCID variants – defined by the presence of residual T cells – are relatively frequent as a consequence of hypomorphic mutation or reversion.

Keywords: severe combined immunodeficiencies; haematopoietic stem cells; T lymphocytes; B lymphocytes; NK lymphocytes; lymphocyte differentiation

Figure 1.

SCID diseases and mechanisms. HSC with self‐renewal capacity can generate lymphocyte precursors such as putative CLP. The latter give rise to NK, T and B lymphocytes. Arrows indicate block in lymphocyte development caused by indicated gene mutations and resulting in a SCID. ADA, adenosine deaminase; PNP, purine nucleoside phosphorylase; Rag‐1/‐2, recombination activating gene 1/2; IL‐7R, interleukin‐7 receptor α chain; JAK‐3, janus kinase 3; HSC, haematopoietic stem cell; CLP, common lymphoid progenitor; NK, .



Aiuti A, Cattaneo F, Galimberti S et al. (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. New England Journal of Medicine 360: 447–458.

Buck D, Malivert L, de Chasseval R et al. (2006) Cernunnos, a novel nonhomologous end‐joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124: 287–299.

Buckley RH (2000) Advances in immunology: primary immunodeficiency diseases due to defects in lymphocytes. New England Journal of Medicine 343: 1313–1324.

Buckley RH (2004) Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annual Review of Immunology 22: 625–655.

van der Burg M, Ijspeert H, Verkaik NS et al. (2009) A DNA‐PKcs mutation in a radiosensitive T‐B‐SCID patient inhibits artemis activation and nonhomologous end‐joining. Journal of Clinical Investigation 119: 91–98.

Cavazzana‐Calvo M, Hacein‐Bey S, de Saint Basile G et al. (2000) Gene therapy of human severe combined immunodeficiency (SCID)‐X1 disease. Science 288: 669–672.

Chase NM, Verbsky JW and Routes JM (2010) Newborn screening for T‐cell deficiency. Current Opinion in Allergy and Clinical Immunology 10: 521–525.

Fischer A (2001) Primary immunodeficiency diseases: an experimental model for molecular medicine. The Lancet 357: 1863–1869.

Fischer A, Le Deist F, Hacein‐Bey‐Abina S et al. (2005) Severe combined immunodeficiency. A model disease for molecular immunology and therapy. Immunological Reviews 203: 98–109.

Hacein‐Bey‐Abina S, Hauer J, Lim A et al. (2010) Efficacy of gene therapy for X‐linked severe combined immunodeficiency. New England Journal of Medicine 363: 355–364.

Lagresle‐Peyrou C, Six EM, Picard C et al. (2009) Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nature Genetics 41: 106–111.

Macchi P, Villa A, Gillani S et al. (1995) Mutations of Jak‐3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377: 65–68.

Moshous D, Callebaut R, de Chasseval R et al. (2001) Artemis, a novel DNA double‐strand break repair/V(D)J recombination protein is mutated in human severe combined immune deficiency with increased radiosensitivity (RS‐SCID). Cell 105: 177–186.

Notarangelo LD, Villa A and Schwarz K (1999) RAG and RAG defects. Current Opinion in Immunology 11: 435–442.

O'Driscoll M, Cerosaletti KM, Girard PM et al. (2001) DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Molecular Cell 8: 1175–1185.

Pannicke U, Honig M, Hess I et al. (2009) Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nature Genetics 41: 101–105.

Puel A, Ziegler SF, Buckley RH and Leonard WJ (1998) Defective IL7R expression in T(−)B(+)NK(+) severe combined immunodeficiency. Nature Genetics 20: 394–397.

Schwarz K, Gauss GH, Ludwig L et al. (1996) RAG mutations in human B cell‐negative SCID. Science 274: 97–99.

Shiow LR, Roadcap DW, Paris K et al. (2008) The actin regulator coronin 1A is mutant in a thymic egress‐deficient mouse strain and in a patient with severe combined immunodeficiency. Nature Immunology 9: 1307–1315.

Further Reading

Bassing CH, Swat W and Alt FW (2002) The mechanism and regulation of chromosomal V(D)J recombination. Cell 109: S45–S55.

Fischer A (2001) Primary immunodeficiency diseases: an experimental model for molecular medicine. Lancet 357: 1863–1869.

Leonard WJ (2001) Cytokines and immunodeficiency diseases. Nature Reviews Immunology 1: 200–208.

Notarangelo LD, Fischer A, Geha RS et al. (2009) Primary immunodeficiencies: 2009 update. Journal of Allergy and Clinical Immunology 124: 1161–1178.

Reith W and Mach B (2001) The bare lymphocyte syndrome and the regulation of MHC expression. Annual Review of Immunology 19: 331–373.

Rooney S, Sekiguchi J, Zhu C et al. (2002) Leaky SCID phenotype associated with defective V(D)J coding end processing in artemis‐deficient mice. Molecular Cell 10: 1379–1390.

Villa A, Santagata S, Bozzi F et al. (1998) Partial V(D)J recombination activity leads to Omenn syndrome. Cell 93: 885–896.

Web Links

Adenosine Deaminase (ADA); MIM Number: 102700. OMIM:‐post/Omim/dispmim?102700

DNA Cross‐link Repair 1C (PSO2 S. cerevisiae) (DCLRE1C); MIM Number: 605988. OMIM:‐post/Omim/dispmim?605988

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Fischer, A(Nov 2011) Severe Combined Immune Deficiency (SCID): Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005941.pub2]