Severe combined immunodeficiency disease: genes and variants

Genes linked to Severe combined immunodeficiency disease

• ADA: Adenosine deaminase

  It degrades adenosine and deoxyadenosine, preventing accumulation of metabolites that are particularly toxic to developing lymphocytes. Biallelic deficiency causes severe combined immunodeficiency, while partial deficiency can present later with immune dysfunction.

  12 disease-causing and 2 uncertain variants in ADA are linked to Severe combined immunodeficiency disease.

• RAG1: V(D)J recombination-activating protein 1

  It initiates V(D)J recombination by cutting antigen-receptor gene segments, creating the enormous receptor diversity required for adaptive immunity. Biallelic severe loss-of-function variants cause severe combined immunodeficiency, while hypomorphic alleles can cause Omenn syndrome or combined immunodeficiency with autoimmunity.

  8 disease-causing and 0 uncertain variants in RAG1 are linked to Severe combined immunodeficiency disease.

• RAG2: V(D)J recombination-activating protein 2

  Together with RAG1, it restricts and activates V(D)J recombination during lymphocyte development so immunoglobulin and T-cell receptor genes can be assembled. Biallelic loss-of-function variants cause severe combined immunodeficiency or hypomorphic immune-dysregulation syndromes.

  7 disease-causing and 0 uncertain variants in RAG2 are linked to Severe combined immunodeficiency disease.

• JAK3: Tyrosine-protein kinase JAK3

  It carries signals from cytokine receptors using the common gamma chain and is essential for T-cell and NK-cell development. Biallelic loss-of-function variants cause severe combined immunodeficiency, while activating somatic variants occur in selected leukemias and lymphomas.

  5 disease-causing and 0 uncertain variants in JAK3 are linked to Severe combined immunodeficiency disease.

• IL7R: Interleukin-7 receptor subunit alpha

  It transmits survival and developmental signals required for T-cell and lymphoid homeostasis. Biallelic loss-of-function variants cause T-cell-negative, B-cell-positive severe combined immunodeficiency, while somatic activating alterations occur in acute lymphoblastic leukemia.

  2 disease-causing and 0 uncertain variants in IL7R are linked to Severe combined immunodeficiency disease.

• DOCK8: Dedicator of cytokinesis protein 8

  It coordinates actin remodeling and signaling required for migration, survival, and immune synapse formation in lymphocytes. Biallelic loss-of-function variants cause DOCK8 deficiency, a combined immunodeficiency characterized by severe viral infections, allergy, eczema, and malignancy risk.

  1 disease-causing and 1 uncertain variants in DOCK8 are linked to Severe combined immunodeficiency disease.

Where Severe combined immunodeficiency disease variants cluster

• RAG1 NBD (positions 392–459): 3 of 8 disease-causing changes, 5.8× more than its size predicts.

Known disease-causing variants in Severe combined immunodeficiency disease

Which prediction tools work for Severe combined immunodeficiency disease

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 95 out of 100
• SIFT: 93 out of 100
• MetaLR: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 83 out of 100

Same protein, different disease

• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency is also caused by ADA variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (44 disease-causing).
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive is also caused by RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (52 disease-causing).
• Combined immunodeficiency with skin granulomas is also caused by RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (49 disease-causing).
• Combined immunodeficiency due to partial RAG1 deficiency is also caused by RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (13 disease-causing).
• Histiocytic medullary reticulosis is also caused by RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (11 disease-causing).
• Recombinase activating gene 1 deficiency is also caused by RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (8 disease-causing).
• Combined immunodeficiency with skin granulomas is also caused by RAG2 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (33 disease-causing).
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive is also caused by RAG2 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (32 disease-causing).
• Recombinase activating gene 2 deficiency is also caused by RAG2 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (25 disease-causing).
• Histiocytic medullary reticulosis is also caused by RAG2 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (14 disease-causing).
• Inborn error of immunity is also caused by RAG2 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (10 disease-causing).
• T-B+ severe combined immunodeficiency due to JAK3 deficiency is also caused by JAK3 variants; they fall mostly in different places as the Severe combined immunodeficiency disease variants (22 disease-causing).

Diseases related to Severe combined immunodeficiency disease

• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, also linked to JAK3, RAG1 and RAG2
• Combined immunodeficiency with skin granulomas, also linked to RAG1 and RAG2
• Histiocytic medullary reticulosis, also linked to RAG1 and RAG2
• T-B+ severe combined immunodeficiency due to JAK3 deficiency, also linked to IL7R and JAK3
• Inherited Immunodeficiency Diseases, also linked to DOCK8 and RAG1
• Hyper-IgE recurrent infection syndrome 1, autosomal dominant, also linked to DOCK8
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, also linked to ADA
• Recombinase activating gene 2 deficiency, also linked to RAG2
• Combined immunodeficiency due to partial RAG1 deficiency, also linked to RAG1
• Inborn error of immunity, also linked to RAG2
• Essential thrombocythemia, also linked to JAK3
• Recombinase activating gene 1 deficiency, also linked to RAG1

Frequently asked questions

Which genes are linked to Severe combined immunodeficiency disease?

In CATVariant, Severe combined immunodeficiency disease is linked to 6 analyzed proteins: ADA (Adenosine deaminase), RAG1 (V(D)J recombination-activating protein 1), RAG2 (V(D)J recombination-activating protein 2), JAK3 (Tyrosine-protein kinase JAK3), IL7R (Interleukin-7 receptor subunit alpha) and DOCK8 (Dedicator of cytokinesis protein 8).

How many genetic variants are linked to Severe combined immunodeficiency disease?

38 variants: 35 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 3 are of uncertain significance or have conflicting reports.

Which uncertain variants in Severe combined immunodeficiency disease look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Severe combined immunodeficiency disease?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 33 disease-causing and 100 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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