Autoimmune lymphoproliferative syndrome: genes and variants

Genes linked to Autoimmune lymphoproliferative syndrome

• FAS: Tumor necrosis factor receptor superfamily member 6

  Its engagement by FAS ligand assembles a death-inducing signaling complex that triggers caspase-mediated apoptosis, particularly in activated lymphocytes. Loss-of-function variants can cause autoimmune lymphoproliferative syndrome by preventing normal contraction of immune responses.

  21 disease-causing and 152 uncertain variants in FAS are linked to Autoimmune lymphoproliferative syndrome.

• KRAS: GTPase KRas

  A small GTPase that acts as a molecular switch in the RAS-MAPK signaling pathway. By cycling between GDP- and GTP-bound states, it relays growth and survival signals, and activating KRAS variants are common drivers of cancer.

  5 disease-causing and 3 uncertain variants in KRAS are linked to Autoimmune lymphoproliferative syndrome.

• CASP8: Caspase-8

  It initiates death-receptor-mediated apoptosis but also regulates lymphocyte activation and inflammatory signaling. Biallelic loss-of-function variants can cause immunodeficiency with defective apoptosis and lymphocyte homeostasis, while somatic pathway alterations can promote cancer-cell survival.

  2 disease-causing and 123 uncertain variants in CASP8 are linked to Autoimmune lymphoproliferative syndrome.

• NRAS: GTPase NRas

  Its active GTP-bound state drives RAF-MEK-ERK and PI3K signaling downstream of growth-factor receptors. Somatic activating variants are common drivers of melanoma, leukemia, and other cancers, while germline activating variants can cause Noonan syndrome.

  0 disease-causing and 1 uncertain variants in NRAS are linked to Autoimmune lymphoproliferative syndrome.

Where Autoimmune lymphoproliferative syndrome variants cluster

• FAS Death (positions 230–314): 14 of 21 disease-causing changes, 2.6× more than its size predicts.

Known disease-causing variants in Autoimmune lymphoproliferative syndrome

Which prediction tools work for Autoimmune lymphoproliferative syndrome

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

• PolyPhen-2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 92 out of 100
• CATVariant: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 84 out of 100
• phyloP: 82 out of 100

Same protein, different disease

• FAS-related autoimmune lymphoproliferative syndrome is also caused by FAS variants; they fall in the same places as the Autoimmune lymphoproliferative syndrome variants (4 disease-causing).
• SQUAMOUS CELL CARCINOMA, BURN SCAR-RELATED, SOMATIC is also caused by FAS variants; they fall partly in the same places as the Autoimmune lymphoproliferative syndrome variants (3 disease-causing).
• RASopathy is also caused by KRAS variants; they fall mostly in different places as the Autoimmune lymphoproliferative syndrome variants (23 disease-causing).
• Noonan syndrome is also caused by KRAS variants; they fall mostly in different places as the Autoimmune lymphoproliferative syndrome variants (16 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by KRAS variants; they fall mostly in different places as the Autoimmune lymphoproliferative syndrome variants (9 disease-causing).
• Non-small cell lung carcinoma is also caused by KRAS variants; they fall mostly in different places as the Autoimmune lymphoproliferative syndrome variants (5 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by KRAS variants; they fall mostly in different places as the Autoimmune lymphoproliferative syndrome variants (4 disease-causing).

Diseases related to Autoimmune lymphoproliferative syndrome

• RASopathy, also linked to KRAS and NRAS
• Noonan syndrome, also linked to KRAS and NRAS
• Noonan syndrome and Noonan-related syndrome, also linked to KRAS and NRAS
• Cardiofaciocutaneous syndrome, also linked to KRAS and NRAS
• Acute myeloid leukemia, also linked to KRAS and NRAS
• Colorectal cancer, also linked to KRAS and NRAS
• Vascular malformation, also linked to KRAS and NRAS
• Juvenile myelomonocytic leukemia, also linked to KRAS and NRAS
• Linear nevus sebaceous syndrome, also linked to KRAS and NRAS
• Hypertrophic cardiomyopathy, also linked to NRAS
• Cardio-facio-cutaneous syndrome, also linked to KRAS
• Familial cancer of breast, also linked to KRAS

Frequently asked questions

Which genes are linked to Autoimmune lymphoproliferative syndrome?

In CATVariant, Autoimmune lymphoproliferative syndrome is linked to 4 analyzed proteins: FAS (Tumor necrosis factor receptor superfamily member 6), KRAS (GTPase KRas), CASP8 (Caspase-8) and NRAS (GTPase NRas).

How many genetic variants are linked to Autoimmune lymphoproliferative syndrome?

354 variants: 28 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 279 are of uncertain significance or have conflicting reports.

Which uncertain variants in Autoimmune lymphoproliferative syndrome 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 Autoimmune lymphoproliferative syndrome?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 12 disease-causing and 10 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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