Study: JGAS00000000099




Titlemutation analysys of Gorlin syndrome
AbstractGorlin 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. Multi-layered mutations in Hh pathway may change the activation level of the Hh signals, which may explain the wide phenotypic variability of Gorlin syndrome.
Study Type
Study TypeExome Sequencing


TitleElucidation of the pathological mechanism of Gorlin syndrome with patient-specific iPS cells
AgencyGrant-in-Aid for Scientific Research (KAKEN)
Grant ID16


PubMed ID28915250
Publication Statuspublished

Study Attribute

NBDC Numberhum0107
Registration date2017-04-04
Submitting organizationTokyo Dental collage
Principal InvestigatorToshifumi Azuma
Molecular Data Typeexome sequencing
PlatformHiseq 2000,Hiseq 4000
Primary PhenotypeOMIM #109400 Basal cell nevus syndrome
DiseaseBasal cell nevus syndrome
DiseaseGorlin syndrome
Accession Title Dataset type Data objects Policy
JGAD00000000099 mutation analysys of Gorlin syndrome Exome sequencing 5 JGAP00000000001