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

Abstract

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.

Identification of Potential Biomarkers Associated with Basal Cell Carcinoma

“…Undén et al found that the expression level of PTCH mRNA was overexpressed in BCC cells compared with nontumor epidermal cells, which was similar to our finding that PTCH1 was upregulated in BCC patients [22]. Interestingly, numerous researchers pointed out that approximately 90% of function mutations in PTCH1 were [24]. A recent investigation has reported that PTCH1 had two mutational statuses (germinal and somatic mutation).…”

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

“…Gorlin-Goltz syndrome (GGS) was first described in 1960 and is alternatively termed Gorlin syndrome, nevoid basal cell carcinoma syndrome (NBCCS), or basal cell nevus syndrome [11]. GGS/NBCCS is a rare condition with an incidence reported as high as 1 in 19,000 births and with nearly complete penetrance but variable expression [11][12][13][14][15][16]. The most frequently observed characteristic is basocellular carcinoma -often with an early onset during the first and second decades of life [12][13][14][15][16].…”

“…GGS/NBCCS is a rare condition with an incidence reported as high as 1 in 19,000 births and with nearly complete penetrance but variable expression [11][12][13][14][15][16]. The most frequently observed characteristic is basocellular carcinoma -often with an early onset during the first and second decades of life [12][13][14][15][16]. The inheritance pattern of GGS/NBCCS is predominantly autosomal dominant [11][12][13][14][15][16]; however, penetrance of the phenotypes is variable in affected relatives [14,15].…”

“…The most frequently observed characteristic is basocellular carcinoma -often with an early onset during the first and second decades of life [12][13][14][15][16]. The inheritance pattern of GGS/NBCCS is predominantly autosomal dominant [11][12][13][14][15][16]; however, penetrance of the phenotypes is variable in affected relatives [14,15]. Loss-of-function mutations in PTCH1 have been identified to cause GGS/ NBCCS [14][15][16].…”

Rare genetic causes of microcephaly and megalencephaly

“…Heterozygous germline PTCH1 mutations cause Gorlin syndrome (OMIM 109400, Gorlin-Goltz syndrome, nevoid basal cell carcinoma, or basal cell nevus syndrome), an autosomal dominant disorder that predisposes affected individuals to developmental defects and tumorigenesis (Kimonis et al, 1997, Gorlin 2004, Pellegrini et al, 2017. Dozens of pathogenic variants in the PTCH1 gene include deletions or insertions, (multi)exon or large-scale deletions or rearrangements resulting in frameshifts, nonsense mutations leading to premature stops, missense, splice-site mutations, and deep intronic variants that alter splicing (Hahn et al, 1996, Lindström et al, 2006, Gianferante et al, 2018. A careful analysis revealed that high frequency of mutations is clustered into the intracellular and two extracellular loops (Lindström et al, 2006).…”