We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Whole‐exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data.
- Authors
Gianferante, D. Matthew; Rotunno, Melissa; Dean, Michael; Zhou, Weiyin; Hicks, Belynda D.; Wyatt, Kathleen; Jones, Kristine; Wang, Mingyi; Zhu, Bin; Goldstein, Alisa M.; Mirabello, Lisa
- Abstract
Background: Nevoid 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. Methods: We 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). Conclusion: Overall, 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. Nevoid basal cell carcinoma syndrome is a rare autosomal dominant disorder, and PTCH1 is the major susceptibility locus. We characterized the clinical information from our NBCCS National Cancer Institute study, available clinical information linked to PTCH1 disease‐causing mutations in Human Gene Mutation Database, and identified nine novel PTCH1 mutations and a genotype–phenotype relationship between developmental delay and gross deletion–insertion mutations.
- Subjects
NUCLEOTIDE sequencing; GENETIC mutation; BASAL cell carcinoma; SINGLE nucleotide polymorphisms; GENOMICS
- Publication
Molecular Genetics & Genomic Medicine, 2018, Vol 6, Issue 6, p1168
- ISSN
2324-9269
- Publication type
Article
- DOI
10.1002/mgg3.498