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First evidence of genotype–phenotype correlations in Gorlin syndrome
  1. D Gareth Evans1,2,
  2. Deemesh Oudit3,
  3. Miriam J Smith1,2,
  4. David Rutkowski1,4,
  5. Ernest Allan3,
  6. William G Newman1,2,4,
  7. John T Lear4
  1. 1 Division of Evolution and Genomic Science, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  2. 2 Manchester Centre for Genomic Medicine, St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
  3. 3 Department of Plastic Surgery, Oncology Christie Hospital, Manchester, UK
  4. 4 Department of Dermatology, MAHSC, Salford Royal Foundation Trust, Salford, UK
  1. Correspondence to Professor D Gareth Evans, Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St Mary’s Hospital, University of Manchester, Manchester M13 9WL, UK; gareth.evans{at}


Background Gorlin syndrome (GS) is an autosomal dominant syndrome characterised by multiple basal cell carcinomas (BCCs) and an increased risk of jaw cysts and early childhood medulloblastoma. Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. Here, we aimed to delineate genotype–phenotype correlations in GS.

Methods We assessed genetic and phenotypic data for 182 individuals meeting the diagnostic criteria for GS (median age: 47.1; IQR: 31.1–61.1). A total of 126 patients had a heterozygous pathogenic variant, 9 had SUFU pathogenic variants and 46 had no identified mutation.

Results Patients with variants were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002) and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003) than patients with no identified mutation. Patients with a missense variant in PTCH1 were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic PTCH1 variants (p=0.03). Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004).

Conclusion We propose that the clinical heterogeneity of GS can in part be explained by the underlying or SUFU variant.

  • PTCH1
  • SUFU
  • Gorlin syndrome
  • medulloblastoma

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  • Contributors DGE planned the study, drafted the manuscript and is responsible for the overall content of the study. MJS carried out in silico analysis and created table 2. DO, MJS, DR, EA, WGN and JTL collated and analysed the data. All authors reviewed, edited and approved the final manuscript.

  • Competing interests None declared.

  • Patient consent Not obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.