Challenging interpretation of low-level PTCH1 mosaicism in patients with clinically diagnosed Gorlin syndrome: a case series and review of the literature

Individuals meeting clinical diagnostic criteria for Gorlin syndrome typically harbor germline pathogenic variants in PTCH1 or SUFU. The molecular basis of a proportion of cases remains unresolved, with mosaicism a possible explanation for some of these unexplained cases. We describe four probands meeting clinical diagnostic criteria for Gorlin syndrome with confirmed mosaic pathogenic variants. The first proband, a 38-year-old male with metastatic basal cell carcinoma and over 30 prior lesions, had no reportable variants identified on peripheral blood DNA. Somatic analysis of a metastatic lymph node identified a pathogenic PTCH1 variant, subsequently detected at low levels (< 3% variant allele frequency (VAF)) in multiple non-tumor tissues, consistent with mosaicism. The second proband, a 39-year-old female with a history of > 250 basal cell carcinomas, had previously undergone PTCH1 and SUFU testing on peripheral blood DNA, with no reportable variants identified. Somatic testing arranged on three basal cell carcinomas identified a common PTCH1 frameshift variant, which on manual re-analysis of peripheral blood DNA was present at < < 1% VAF. Two additional probands, a 32-year-old female and a 30-year-old male, had a PTCH1 variant reported at 11% and 15% VAF, respectively, in peripheral blood DNA. The clinical features of these individuals are described and compared with 11 additional mosaic probands with confirmed PTCH1 variants and/or clinically diagnosed Gorlin syndrome identified from the literature. The presented case series and accompanying literature review provide the largest summary to date of the spectrum of clinical features observed due to PTCH1 mosaicism. Importantly, it highlights the possibility that low-level PTCH1 mosaicism may still result in a classic Gorlin syndrome phenotype. This review reinforces the importance of additional testing of multiple tissue types to achieve a molecular diagnosis, given the implications for familial risk assessment, reproductive planning, and to support access to targeted systemic therapies.