Which genetic mutations cause severe combined immunodeficiency (SCID)?

Updated: Apr 28, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD  more...
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Answer

Mutational analysis pinpoints many types of SCID: more than 20 genetic loci are referenced in the Online Mendelian Inheritance in Man (OMIM) database. Large deletions of chromosomal material are not seen, and this limits the techniques that can be applied for mutation detection. In general, specific mutations do not predict the degree of severity of a specific form of SCID.

Overall, SCID is characterized by profound abnormalities in T-cell, B-cell, and NK-cell functions. The genetic mutations can be X-linked, autosomal recessive, or sporadic, depending on the location of the gene affected. Although the list of gene defects is extensive, the disease can be stratified according to absence of T-cell function with or without the loss of B- and NK-cell host defenses (see Table 1 below).

Table 1. Common Causes of SCID, Cellular Defects, and Inheritance Pattern (Open Table in a new window)

Genetic Disease Causing SCID

T-Cell Defect

B-Cell Defect

NK-Cell Defect

Inheritance Pattern

Reticular dysgenesis

Yes

Yes

Yes

Autosomal recessive

ADA deficiency

Yes

Yes

Yes

Autosomal recessive

RAG1 and RAG2 deficiency

Yes

Yes

No

Autosomal recessive

TCR and BCR recombination gene deficiency

Yes

Yes

No

Autosomal recessive

Common γ chain deficiency

Yes

No

Yes

X-linked

JAK3 deficiency

Yes

No

No

Autosomal recessive

IL-7Ra deficiency

Yes

No

No

Autosomal recessive

Omenn syndrome

Yes

No

No

Autosomal recessive

ZAP-70 kinase

CD4+ present

No

No

Autosomal recessive

CD4+ lymphopenia

CD8+ present

No

No

Autosomal recessive

MHC II deficiency

CD8+ present

No

No

Autosomal recessive

p56lck deficiency

CD8+ present

No

No

Autosomal recessive

ADA = adenosine deaminase; BCR = B-cell receptor; JAK = Janus-associated kinase; MHC = major histocompatibility complex; RAG = recombination-activating gene; SCID = severe combined immunodeficiency; TCR = T-cell receptor, ZAP = ζ chain-associated protein.

SCID is most commonly due to an X-linked mutation of the gene coding for the γ chain that is common to the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. XL-SCID accounts for approximately 50% of all cases of SCID. Mutations in the intracellular tail of the common γ chain are associated with a less severe form of XL-SCID. Defective expression of the common γ chain can be detected by flow cytometry. SCID has also been described due to compound heterozygous mutations in the MTHFD1 gene. [31] Hydroxocobalamin and folate therapy provided partial immune reconstitution.

The remainder of SCID cases result from the following autosomal recessive or, less commonly, sporadic mutations:

  • ADA and PNP deficiencies

  • Mutation of the IL-7R α chain

  • IL-2 production defects

  • Mutation of JAK3

  • Null mutations in RAG1 and RAG2

  • Artemis gene mutations

  • CD45 mutations

  • Mutations of ZAP70

  • CD3γ, ε, and δ mutations

  • MHC class II deficiency caused by mutations of components of the transcription factors of MHC II, including CIITA

  • Bare lymphocyte syndrome

  • Deficiency in p56lck (a tyrosine kinase–signaling molecule in the IL-2–mediated JAK-STAT pathway)

  • Cartilage-hair hypoplasia


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