PTCH2 is not a strong candidate gene for gorlin syndrome predisposition

Area of Science:

• Genetics and Genomics
• Molecular Biology
• Clinical Genetics

Background:

• Gorlin Syndrome (GS), also known as nevoid basal cell carcinoma syndrome, is a genetic disorder.
• Previous reports suggested PTCH2 as a potential gene involved in GS, but conclusive evidence was lacking.
• Genetic testing for GS typically involves analyzing genes like PTCH1 and SUFU.

Purpose of the Study:

• To investigate the role of PTCH2 in Gorlin Syndrome.
• To evaluate the pathogenicity of PTCH2 variants in a cohort of PTCH1/SUFU-negative GS families.
• To assess existing evidence for PTCH2 as a GS gene.

Main Methods:

• Genetic analysis of PTCH2 variants in a cohort of 21 PTCH1 and SUFU negative Gorlin Syndrome families.
• Review and re-evaluation of previously reported PTCH2 variants in GS cases using current pathogenicity guidelines.
• Analysis of population data to determine the frequency of PTCH2 loss-of-function variants.

Main Results:

• No pathogenic or likely pathogenic PTCH2 variants were identified in the PTCH1/SUFU negative GS cohort.
• Previously reported PTCH2 variants associated with GS did not meet criteria for pathogenicity.
• Loss-of-function PTCH2 variants are common in the general population, including homozygous instances without clinical symptoms.

Conclusions:

• PTCH2 is not a causative gene for Gorlin Syndrome.
• The high frequency of PTCH2 loss-of-function variants in the general population argues against its role in GS.
• PTCH2 should be excluded from genetic testing panels for Gorlin Syndrome diagnosis.