title: Large germline deletions of the CYLD gene in patients with Brooke-Spiegler syndrome and multiple familial trichoepithelioma.
abstract: Brooke-Spiegler syndrome (BSS) and its phenotypic variants, multiple familial trichoepithelioma (MFT) and familial cylindromatosis, are rare autosomal dominant hereditary diseases. They are characterized by the presence of multiple adnexal tumors, especially cylindromas, spiradenomas, spiradenocylindromas, and trichoepitheliomas. Implicated in the pathogenesis of the disease is the gene CYLD, which is localized on the long arm of chromosome 16. This gene encodes an evolutionarily conserved protein belonging to the deubiquitinating enzymes family, which plays a key role in many signaling pathways, especially in NF-κB, JNK, and Wnt. Less than 90 germline mutations of CYLD have been identified in patients with BSS/MFT. These mutations are mostly small alterations in the coding sequence and at exon-intron junction sites. One patient with an intronic mutation and another with a large CYLD deletion have also been recorded. In this study, the authors have analyzed a cohort of 14 patients with BSS/MFT from 13 families for large genome rearrangements by array comparative genome hybridization followed by confirmatory sequencing. We identified 2 large deletions, namely c.-34111_*297858del378779 and c.914-6398_1769del13642ins20 in patients with MFT and BSS, respectively. All other analyzable patients did not reveal any copy number alteration. It is concluded that the large rearrangements are relatively rare in patients without a germline CYLD mutation demonstrable by conventional sequencing. The pathogenetic mechanisms in patients with BSS/MFT lacking germline sequence alterations or large rearrangements in the CYLD gene remain to be clarified.
authors.affiliation: *Bioptical Laboratory, Pilsen, Czech Republic; †Central European Biosystems, Prague, Czech Republic; ‡Sikl's Department of Pathology, Medical Faculty in Pilsen, Charles University in Prague, Pilsen, Czech Republic; §Department of Pathology, Warwick Hospital, Warwick, United Kingdom; and ¶Ear, Nose, and Throat Clinic, Medical Faculty in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Vanecek
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Halbhuber
authors.forename: Denisa
authors.initials: D
authors.lastname: Kacerovska
authors.forename: Petr
authors.initials: P
authors.lastname: Martinek
authors.forename: Monika
authors.initials: M
authors.lastname: Sedivcova
authors.forename: Richard A
authors.initials: RA
authors.lastname: Carr
authors.forename: David
authors.initials: D
authors.lastname: Slouka
authors.forename: Michal
authors.initials: M
authors.lastname: Michal
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Kazakov
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD