First evidence of genotype-phenotype correlations in Gorlin syndrome

Gorlin syndrome (GS) is an autosomal dominant syndrome characterised by multiple basal cell carcinomas and an increased risk of jaw cysts and medulloblastoma in early life. Heterozygous germline variants in Patch1 (PTCH1) and SUFU encoding components of the Sonic Hedgehog pathway (SHH) explain the majority of cases. Here we have undertaken a genotype-phenotype correlation of 182 individuals Median age 47.1 (IQR: 31.1-61.1) meeting diagnostic criteria for GS. A total of 126 patients had a heterozygous pathogenic PTCH1 variant, 9 had SUFU pathogenic variants and 46 had no identified mutation. Patients with PTCH1 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). In summary, we propose that the clinical heterogeneity of GS can in part be explained by the underlying PTCH1 or SUFU variant.