Wiskott-Aldrich syndrome: genes and variants

Genes linked to Wiskott-Aldrich syndrome

• WAS: Actin nucleation-promoting factor WAS

  It couples signaling from immune receptors to actin-cytoskeleton remodeling, enabling immune synapse formation, cell migration, and normal platelet production. Loss-of-function variants cause Wiskott-Aldrich syndrome or X-linked thrombocytopenia, while activating variants can cause severe congenital neutropenia.

  28 disease-causing and 146 uncertain variants in WAS are linked to Wiskott-Aldrich syndrome.

• WRN: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN

  It combines DNA helicase and exonuclease activities to maintain replication forks, telomeres, and genome stability. Biallelic loss-of-function variants cause Werner syndrome, an adult-onset progeroid disorder with premature aging, metabolic disease, atherosclerosis, and increased cancer risk.

  0 disease-causing and 3 uncertain variants in WRN are linked to Wiskott-Aldrich syndrome.

Where Wiskott-Aldrich syndrome variants cluster

• WAS WH1 (positions 39–148): 21 of 28 disease-causing changes, 3.4× more than its size predicts.

Known disease-causing variants in Wiskott-Aldrich syndrome

Which prediction tools work for Wiskott-Aldrich syndrome

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

• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 94 out of 100
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Diseases related to Wiskott-Aldrich syndrome

• Ovarian cancer, also linked to WRN
• X-linked severe congenital neutropenia, also linked to WAS
• Werner syndrome, also linked to WRN

Frequently asked questions

Which genes are linked to Wiskott-Aldrich syndrome?

In CATVariant, Wiskott-Aldrich syndrome is linked to 2 analyzed proteins: WAS (Actin nucleation-promoting factor WAS) and WRN (Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN).

How many genetic variants are linked to Wiskott-Aldrich syndrome?

226 variants: 28 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 149 are of uncertain significance or have conflicting reports.

Which uncertain variants in Wiskott-Aldrich 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 Wiskott-Aldrich syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 27 disease-causing and 37 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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