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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.
AuthorsTomas Vanecek, Zbynek Halbhuber, Denisa Kacerovska, Petr Martinek, Monika Sedivcova, Richard A Carr, David Slouka, Michal Michal, Dmitry V Kazakov
JournalThe American Journal of dermatopathology (Am J Dermatopathol) Vol. 36 Issue 11 Pg. 868-74 (Nov 2014) ISSN: 1533-0311 [Electronic] United States
PMID25347032 (Publication Type: Journal Article)
Chemical References
  • Biomarkers, Tumor
  • Tumor Suppressor Proteins
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD
Topics
  • Adolescent
  • Adult
  • Base Sequence
  • Biomarkers, Tumor (genetics)
  • Biopsy
  • Comparative Genomic Hybridization
  • DNA Mutational Analysis
  • Deubiquitinating Enzyme CYLD
  • Female
  • Gene Rearrangement
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Humans
  • INDEL Mutation
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Neoplastic Syndromes, Hereditary (genetics, pathology)
  • Pedigree
  • Phenotype
  • Sequence Deletion
  • Skin Neoplasms (genetics, pathology)
  • Tumor Suppressor Proteins (genetics)
  • Young Adult

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