Waardenburg syndrome: genes and variants

Genes linked to Waardenburg syndrome

• SOX10: Transcription factor SOX-10

  23 disease-causing and 19 uncertain variants in SOX10 are linked to Waardenburg syndrome.

• MITF: Microphthalmia-associated transcription factor

  10 disease-causing and 242 uncertain variants in MITF are linked to Waardenburg syndrome.

• EDNRB: Endothelin receptor type B

  3 disease-causing and 11 uncertain variants in EDNRB are linked to Waardenburg syndrome.

Where Waardenburg syndrome variants cluster

• SOX10 HMG box (positions 104–172): 22 of 23 disease-causing changes, 6.5× more than its size predicts.
• MITF bHLH (positions 311–364): 6 of 10 disease-causing changes, 5.8× more than its size predicts.

Known disease-causing variants in Waardenburg syndrome

Uncertain variants in Waardenburg syndrome that look disease-causing

Which prediction tools work for Waardenburg syndrome

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

• CADD: 98 out of 100
• SIFT: 97 out of 100
• PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 67 out of 100

Diseases related to Waardenburg syndrome

• Rare genetic deafness, also linked to SOX10
• Pulmonary arterial hypertension, also linked to EDNRB
• Hirschsprung disease, also linked to EDNRB
• Melanoma, cutaneous malignant, susceptibility to, 8, also linked to MITF
• PCWH syndrome, also linked to SOX10
• Melanoma, also linked to MITF
• Tietz syndrome, also linked to MITF
• Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness, also linked to MITF

Frequently asked questions

Which genes are linked to Waardenburg syndrome?

In CATVariant, Waardenburg syndrome is linked to 3 analyzed proteins: SOX10 (Transcription factor SOX-10), MITF (Microphthalmia-associated transcription factor) and EDNRB (Endothelin receptor type B).

How many genetic variants are linked to Waardenburg syndrome?

379 variants: 36 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 272 are of uncertain significance or have conflicting reports.

Which uncertain variants in Waardenburg syndrome look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SOX10 R161H and SOX10 M112V. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Waardenburg syndrome?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 9 disease-causing and 23 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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