First evidence of genotype-phenotype correlations in Gorlin syndrome.

Abstract

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 <i>PTCH1</i> and <i>SUFU</i> encoding components of the Sonic hedgehog pathway explain the majority of cases. Here, we aimed to delineate genotype-phenotype correlations in GS. 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 <i>SUFU</i> pathogenic variants and 46 had no identified mutation. 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 <i>PTCH1</i> were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic <i>PTCH1</i> variants (p=0.03). Patients with <i>SUFU</i> pathogenic variants were significantly more likely than those with <i>PTCH1</i> 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). We propose that the clinical heterogeneity of GS can in part be explained by the underlying or <i>SUFU</i> variant.