engleski

Different types of PTCH1 gene mutations in Gorlin syndrome in Croatia

Gorlin syndrome or Basal Cell Nevus Syndrome (BCNS) is a rare autosomal dominant disorder characterized by developmental malformations and predisposition to various tumors with basal cell carcinomas being the most common, followed by medulloblastomas, meningiomas and ovarian and heart fibromas. The syndrome is associated with a bewildering range of clinical signs and symptoms. The estimated prevalence is between 1:57.000 and 1:256.000. The syndrome is predominately caused by mutations in PTCH1, a tumor suppressor gene located at 9q22.32. The purpose of this study was to estimate the spectrum of mutation types characteristic for the Gorlin syndrome found in Croatia. All coding exons and promoter region of PTCH1 gene from 14 candidates (11 families) were scanned for mutations using High-resolution melting analysis (HRMA), Quantitative multiplex PCR of short fluorescent fragments (QMPSF), long range PCR and sequencing. Several different types of mutations were found. In one patient a large deletion of 4.5 Mb in the 9q22.32–q22.33 region was determined, and included the entire PTCH1 gene and also 22 other OMIM genes. In one family, the duplication was in exon 7: c.1043_1046dupAGAA (p.Asn349Lysfs*87). In another family, the deletion c.3011del11 (p.Gln1004Leufs*7) was in exon 18. In one patient, a substitution: c.590G>A (p.Trp197*) in exon 4 was determined to be pathogenic. In two more patients substitutions were also found, but since one, c.2073C>T (p.Thr691Thr) is synonymous, and the other c.3449+10C>T, intronic, the clinical significance could not be determined. To detect all mutations found in the Gorlin syndrome, the combination of QMPSF and HRMA methods is necessary to provide complete coverage of all mutation types.

mutations; Gorlin syndrome; mutation detection methods

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