PTCH1 – Gorlin Syndrome (Nevoid Basal Cell Carcinoma Syndrome)

Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder characterized by multiple basal cell carcinomas, odontogenic keratocysts, palmar/plantar pits and calcification of the falx cerebri (HP:0005462). Germline mutations in PTCH1, encoding the Hedgehog receptor Patched-1, underlie the vast majority of cases. Diagnostic criteria include two major findings or one major plus two minor features, and molecular confirmation is achieved by identifying a pathogenic PTCH1 variant in affected individuals.

Genetic evidence for PTCH1–Gorlin syndrome is definitive. Over 300 probands from more than 100 unrelated families harbor a spectrum of PTCH1 variants (PMID:8981943), including truncating frameshifts, nonsense and splice-site changes, as well as missense mutations within functional domains. Loss-of-function alleles constitute ~86% of reported variants, consistent with haploinsufficiency. Common recurrent variants and de novo mutations account for ~50% of cases, while inherited alleles segregate with disease in multiplex pedigrees.

Segregation analysis across multiple family series confirms autosomal dominant transmission. In a cohort of 106 pedigrees with ≥2 cardinal manifestations, 47 families had PTCH1 mutations detected by sequencing and MLPA (PMID:16301862). In a Chinese kindred, a heterozygous c.897G>A (p.Glu236Lys) change was present in all four affected relatives and absent in unaffected members and controls (PMID:21514272).

Functional/experimental studies support PTCH1 loss leading to aberrant Hedgehog pathway activation. Several missense mutations impair protein maturation or trafficking, abrogating repression of Gli transcription factors (PMID:12670916; PMID:12072433). In Ptch1-deficient fibroblasts, wild-type PTCH1 restores Shh-responsive LacZ reporter repression, whereas tumor-derived PTCH1 mutants fail to inhibit signaling, confirming loss-of-function and dominant-negative effects.

Although SUFU and PTCH2 variants can phenocopy Gorlin features, PTCH1 remains the primary genetic contributor. SUFU mutations account for a minority of PTCH1-negative families and confer a distinct spectrum with higher medulloblastoma risk (PMID:25403219). No studies have refuted the PTCH1–Gorlin association.

Integration of extensive case reports, segregation data and concordant functional assays establishes a definitive clinical validity of PTCH1 in Gorlin syndrome. Genetic testing for PTCH1 variants is essential for diagnostic confirmation, familial risk assessment and guiding surveillance. Key take-home: PTCH1 haploinsufficiency via truncating or missense mutations disrupts Hedgehog repression to cause Gorlin syndrome with high penetrance and variable expressivity.

References

• American journal of human genetics • 1997 • Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident. PMID:8981943
• Genetics in medicine : official journal of the American College of Medical Genetics • 2005 • Clinical testing for the nevoid basal cell carcinoma syndrome in a DNA diagnostic laboratory. PMID:16301862
• Biochemical and biophysical research communications • 2003 • Several human PATCHED1 mutations block protein maturation. PMID:12670916

Evidence Based Scoring (AI generated)