Gorlin syndrome: genes and variants

Genes linked to Gorlin syndrome

• PTCH1: Protein patched homolog 1

  It suppresses Smoothened in the absence of Hedgehog ligands and thereby keeps Hedgehog developmental signaling inactive until an appropriate signal is received. Germline loss-of-function variants cause Gorlin syndrome, while somatic pathway activation drives basal-cell carcinoma and other tumors.

  27 disease-causing and 1,834 uncertain variants in PTCH1 are linked to Gorlin syndrome.

• SUFU: Suppressor of fused homolog

  It restrains GLI transcription factors and thereby keeps Hedgehog signaling off when pathway activation is absent. Germline loss-of-function variants predispose particularly to infant desmoplastic medulloblastoma and can also cause developmental Hedgehog-pathway phenotypes.

  0 disease-causing and 523 uncertain variants in SUFU are linked to Gorlin syndrome.

Where Gorlin syndrome variants cluster

• PTCH1 Transmembrane (positions 501–519): 6 of 27 disease-causing changes, 16.9× more than its size predicts.
• PTCH1 Transmembrane (positions 1152–1174): 3 of 27 disease-causing changes, 7.0× more than its size predicts.

Known disease-causing variants in Gorlin syndrome

Uncertain variants in Gorlin syndrome that look disease-causing

Which prediction tools work for Gorlin syndrome

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

• AlphaMissense: 99 out of 100
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 93 out of 100
• SIFT: 91 out of 100

Diseases related to Gorlin syndrome

• Medulloblastoma, also linked to PTCH1 and SUFU
• Basal cell nevus syndrome 1, also linked to PTCH1 and SUFU
• Ovarian cancer, also linked to PTCH1
• Familial meningioma, also linked to SUFU
• Joubert syndrome, also linked to SUFU
• Basal cell carcinoma, also linked to PTCH1
• Holoprosencephaly, also linked to PTCH1

Frequently asked questions

Which genes are linked to Gorlin syndrome?

In CATVariant, Gorlin syndrome is linked to 2 analyzed proteins: PTCH1 (Protein patched homolog 1) and SUFU (Suppressor of fused homolog).

How many genetic variants are linked to Gorlin syndrome?

2,459 variants: 27 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2,357 are of uncertain significance or have conflicting reports.

Which uncertain variants in Gorlin syndrome look disease-causing?

7 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example PTCH1 A569V, PTCH1 A569T, PTCH1 T499I, PTCH1 G445D and PTCH1 A569G. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Gorlin syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 24 disease-causing and 26 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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