Novel clinical and molecular findings in Spanish patients with naevoid basal cell carcinoma syndrome

[Background]: Naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental alterations and multiple basal cell carcinomas. Mutations in PTCH1, which encodes a membrane receptor for Sonic Hedgehog, are associated with the development of the disease. Most of them produce a truncated protein, which is unable to suppress Smoothened protein and continuously activates the downstream pathway. [Objectives]: We aimed to characterize 22 unrelated Spanish patients with NBCCS, the largest cohort with Gorlin syndrome reported to date in Spain. [Methods]: Genomic analysis of PTCH1 was performed in patients with NBCCS and controls, and mutations were analysed using bioinformatics tools. [Results]: We report for the first time two young patients, one each with uterus didelphys and ganglioneuroma, within the context of NBCCS. One patient showing a severe phenotype of the disease had developed basal cell carcinomas since childhood. Sanger sequencing of PTCH1 in this cohort identified 17 novel truncating mutations (11 frameshift, five nonsense and one mutation affecting an exon–intron splice site) and two novel missense mutations that were predicted to be pathogenic. The patients showed great clinical variability and inconsistent genotype–phenotype correlation, as seen in relatives carrying similar mutations. [Conclusions]: This study contributes to increase the pool of clinical manifestations of NBCCS, as well as increasing the number of pathogenic mutations identified in PTCH1 predisposing to the condition. The inconsistencies found between phenotype and genotype suggest the involvement of other modifying factors, genetic, epigenetic or environmental.This project was funded by Fundación Rodríguez Pascual, Consejería de Sanidad de la Junta de Castilla y León‐FEDER (GRS165/A/07) and ISCIII‐FEDER (PI10/00219 and PI13/01741). The research at the Melanoma Unit in Barcelona was partially funded by grants 12/00840 from Fondo de Investigaciones Sanitarias, Spain; by the CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; by the AGAUR 2014_SGR_603 of the Catalan Government, Spain; by a grant from ‘Fundació La Marató de TV3, 201331‐30’, Catalonia, Spain; and by the European Commission under the 6th Framework Programme, contract no. LSHC‐CT‐2006‐018702 (GenoMEL), under the 7th Framework Programme (Diagnoptics). J.C. is partially supported by grant GRS 1342/A/16 (Gerencia Regional de Salud de Castilla y León) and by the program INT/M/16/17 from the Gerencia Regional de Salud de Castilla y León.Peer Reviewe