Multi-layered mutation in hedgehog-related genes in Gorlin syndrome may affect the phenotype

Abstract

Gorlin syndrome is a genetic disorder of autosomal dominant inheritance that predisposes the affected individual to a variety of disorders that are attributed largely to heterozygous germline patched1 (PTCH1) mutations. PTCH1 is a hedgehog (Hh) receptor as well as a repressor, mutation of which leads to constitutive activation of Hh pathway. Hh pathway encompasses a wide variety of cellular signaling cascades, which involve several molecules; however, no associated genotype-phenotype correlations have been reported. Recently, mutations in Suppressor of fused homolog (SUFU) or PTCH2 were reported in patients with Gorlin syndrome. These facts suggest that multi-layered mutations in Hh pathway may contribute to the development of Gorlin syndrome. We demonstrated multiple mutations of Hh-related genes in addition to PTCH1, which possibly act in an additive or multiplicative manner and lead to Gorlin syndrome. High-throughput sequencing was performed to analyze exome sequences in four unrelated Gorlin syndrome patient genomes. Mutations in PTCH1 gene were detected in all four patients. Specific nucleotide variations or frameshift variations of PTCH1 were identified along with the inferred amino acid changes in all patients. We further filtered 84 different genes which are closely related to Hh signaling. Fifty three of these had enough coverage of over ×30. The sequencing results were filtered and compared to reduce the number of sequence variants identified in each of the affected individuals. We discovered three genes, PTCH2, BOC, and WNT9b, with mutations with a predicted functional impact assessed by MutationTaster2 or PolyPhen-2 (Polymorphism Phenotyping v2) analysis. It is noticeable that PTCH2 and BOC are Hh receptor molecules. No significant mutations were observed in SUFU.

Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research

“…Recently, it was shown that, in GS, causative gene mutations may exist in both PTCH1 and PTCH2 simultaneously. Onodera et al [ 34 ] detected mutations in PTCH2, BOC , and WNT9b genes along with PTCH1 by exome sequence analysis. These mutations are predicted to have a functional impact by programs called MutationTaster and Polyphen2 (Polymorphism Phenotyping v2), a web-based program to evaluate DNA sequence variants for their disease-causing potential.…”

“…These mutations are predicted to have a functional impact by programs called MutationTaster and Polyphen2 (Polymorphism Phenotyping v2), a web-based program to evaluate DNA sequence variants for their disease-causing potential. These results indicate that some patients with GS might have mutilayered mutations in the Hh signaling pathway [ 34 ].…”

Novel SUFU Frameshift Variant Leading to Meningioma in Three Generations in a Family with Gorlin Syndrome

“…However, another possibility is that the difference in phenotype between these case series was due to multilayered variants in genes related to the hedgehog pathway as hypothesized by Onodera et al . [10], radiation exposure, and possibly pigmentation genes. In Onodera et al's study of four patients with GS and PTCH1 variants they found that all patients had additional variants in genes related to the hedgehog pathway [10].…”

“…SUFU pathogenic variants are associated with a higher rate of meningiomas and medulloblastomas compared to PTCH1 [4, 9]. Studies have also shown that some of the variability seen in GS might be due to multilayered genetic variants in the hedgehog pathway related genes [10].…”

The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview

“…The missing relationship between the genotype and the phenotype suggests the existence of a very complex variability of this syndrome, possibly originated by the interaction of genetic background and environmental factors [2,44,45]. However, it has been proposed that additional simultaneous mutation may contribute to phenotype variation [46].…”