First evidence of genotype–phenotype correlations in Gorlin syndrome

Evans, D. Gareth; Oudit, Deemesh; Smith, Miriam J.; Rutkowski, David; Allan, Ernest; Newman, William G.; Lear, John T.

doi:10.1136/jmedgenet-2017-104669

Cited by 65 publications

(109 citation statements)

References 37 publications

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“…We investigated whether there were any genotype–phenotype relationships with PTCH1 mutations by gene domains or mutation type. Consistent with previous reports (Evans et al, ; Ikemoto et al, ; Kato et al, ; Okamoto et al, ), we found no hot spots or strong genotype–phenotype relationships. There was a suggestive association between falx cerebri calcifications and all transmembrane domains, although not statistically significant using a more conservative Bonferroni correction for multiple comparison.…”

Section: Discussionsupporting

confidence: 93%

“…Germline mutations in two other genes, SUFU (OMIM 607035) and PTCH2 (OMIM 603673), have also been reported to cause rare cases of NBCCS. Both genes are negative regulators of the SHH pathway (Bresler et al, 2016;Evans et al, 2017;Fan et al, 2008;Fujii et al, 2013;Pastorino et al, 2009;Rimkus et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Extracellular 1 and extracellular 4 domains have been suggested to be important for SHH binding (Marigo, Davey, Zuo, Cunningham, & Tabin, 1996). However, pathogenic mutations are rarely shared among unrelated families, and no specific hot spots or genotype-phenotype correlations have been identified (Evans et al, 2017;Ikemoto et al, 2017;Kato et al, 2017;Okamoto, Naruto, Kohmoto, Komori, & Imoto, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Whole‐exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data

Gianferante

Rotunno

Dean

et al. 2018

Molec Gen & Gen Med

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BackgroundNevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with variable expression and nearly complete penetrance. PTCH1 is the major susceptibility locus and has no known hot spots or genotype–phenotype relationships.MethodsWe evaluated 18 NBCCS National Cancer Institute (NCI) families plus PTCH1 data on 333 NBCCS disease‐causing mutations (DM) reported in the Human Gene Mutation Database (HGMD). National Cancer Institute families underwent comprehensive genomic evaluation, and clinical data were extracted from NCI and HGMD cases. Genotype–phenotype relationships were analyzed using Fisher's exact tests focusing on mutation type and PTCH1 domains.Results PTCH1 pathogenic mutations were identified in 16 of 18 NCI families, including three previously mutation‐negative families. PTCH1 mutations were spread across the gene with no hot spot. After adjustment for multiple tests, a statistically significant genotype–phenotype association was observed for developmental delay and gross deletion–insertions (p = 9.0 × 10−6), and suggestive associations between falx cerebri calcification and all transmembrane domains (p = 0.002) and severe outcomes and gross deletion–insertions (p = 4.0 × 10−4).ConclusionOverall, 89% of our NCI families had a pathogenic PTCH1 mutation. The identification of PTCH1 mutations in previously mutation‐negative families underscores the importance of repeated testing when new technologies become available. Additional clinical information linked to mutation databases would enhance follow‐up and future studies of genotype–phenotype relationships.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Whole‐exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data

Gianferante

Rotunno

Dean

et al. 2018

Molec Gen & Gen Med

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“…No association between the genetic variant and phenotype of this disease has been observed. Exons 2 to 21 were evenly distributed, and no clear hotspots were observed [ 27 , 28 ]. The most common form of mutation is frameshift mutation, followed by nonsense mutation, leading to the premature termination of PTCH1 translation ( Table S1 ).…”

Section: Genetic and Molecular Structural Aspects Of Gorlin Syndromentioning

confidence: 99%

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

Onodera

Nakamura

2020

IJMS

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Gorlin syndrome is a skeletal disorder caused by a gain of function mutation in Hedgehog (Hh) signaling. The Hh family comprises of many signaling mediators, which, through complex mechanisms, play several important roles in various stages of development. The Hh information pathway is essential for bone tissue development. It is also the major driver gene in the development of basal cell carcinoma and medulloblastoma. In this review, we first present the recent advances in Gorlin syndrome research, in particular, the signaling mediators of the Hh pathway and their functions at the genetic level. Then, we discuss the phenotypes of mutant mice and Hh signaling-related molecules in humans revealed by studies using induced pluripotent stem cells.

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“…The genotype-phenotype correlation is difficult to establish for NBCCS. Patients with SUFU mutation were significantly more likely to develop a medulloblastoma than those with PTCH1 mutations; however, they were less likely to develop odontogenic keratocysts [Evans et al, 2017].…”

mentioning

confidence: 93%

A Novel <b><i>PTCH1 </i></b>Frameshift Mutation Leading to Nevoid Basal Cell Carcinoma Syndrome

Durmaz

Evans

Smith

et al. 2018

Cytogenet Genome Res

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Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare multisystemic autosomal dominant disorder typically presenting with cutaneous basal cell carcinomas, multiple keratocysts, and skeletal anomalies. NBCCS is caused by heterozygous mutations in the PTCH1 gene in chromosome 9q22, in the PTCH2 gene in 1p34, or the SUFU gene in 10q24.32. Here, we report on an 18-month-old boy presenting with medulloblastoma, frontal bossing, and multiple skeletal anomalies and his father who has basal cell carcinomas, palmar pits, macrocephaly, bifid ribs, calcification of falx cerebri, and a history of surgery for odontogenic keratocyst. These clinical findings were compatible with the diagnosis of NBCCS, and a novel mutation, c.1249delC; p.Gln417Lysfs*15, was found in PTCH1 causing a premature stop codon.

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First evidence of genotype–phenotype correlations in Gorlin syndrome

Abstract: We propose that the clinical heterogeneity of GS can in part be explained by the underlying or variant.

Cited by 65 publications

References 37 publications

Whole‐exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data

Whole‐exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data

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

A Novel <b><i>PTCH1 </i></b>Frameshift Mutation Leading to Nevoid Basal Cell Carcinoma Syndrome

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