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. 2018 Nov;6(6):1168-1180.
doi: 10.1002/mgg3.498. Epub 2018 Nov 8.

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

D Matthew Gianferante  1 , Melissa Rotunno  2 , Michael Dean  1 , Weiyin Zhou  3 , Belynda D Hicks  1   3 , Kathleen Wyatt  3 , Kristine Jones  1   3 , Mingyi Wang  3 , Bin Zhu  3 , Alisa M Goldstein  1 , Lisa Mirabello  1
Affiliations

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

D Matthew Gianferante et al. Mol Genet Genomic Med. 2018 Nov.

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.

Keywords: PTCH1; genotype-phenotype; nevoid basal cell carcinoma syndrome; pathogenic mutations; whole-exome sequencing.

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Figures

Figure 1
Figure 1
National Cancer Institute study population by PTCH1 mutation testing type and results. Schematic of the 18 families in the NCI cohort and PTCH1 mutation testing by DNA test type. Letters and numbers within the boxes identify different families. All families without a pathogenic PTCH1 mutation on targeted sequencing or WES were further screened by either aCGH or SNP array to evaluate for large deletions. aCGH: array comparative genomic hybridization; SNP: single nucleotide polymorphism; WES: whole‐exome sequencing
Figure 2
Figure 2
Distribution of PTCH1 mutations by protein domains in NCI and HGMD patients. Mutations above the gene are from HGMD samples; below are mutations from NCI patients. cDNA position based on transcript NM_000264.3. Dotted lines indicate exon boundaries. Different shades of gray, white, and black represent different PTCH1 protein domains: C/N‐terminal = black, transmembrane domains = white, extracellular = dark gray, and intracellular domains = light gray
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