Identification of putative phenotype-modifying genetic factors associated with phenotypic diversity in Brooke-Spiegler syndrome

Abstract Background: Brooke-Spiegler syndrome (BSS; OMIM 605041) is a rare monogenic skin disease characterized by the development of skin appendage tumors caused by mutations in the cylindromatosis (CYLD) gene. Despite the described phenotypes and reports of the underlying CYLD mutations, it has been difficult to establish genotype–phenotype correlations in BSS. We recently investigated two BSS pedigrees (Hungarian with Bukovinian origin and Anglo-Saxon), in which the affected family members exhibit striking differences in their phenotypes — despite carrying the same disease-causing mutation (c.2806C>T, p.Arg936Ter) of the CYLD gene. The aim of our study was to identify phenotype-modifying genetic factors to further the understanding of genotype–phenotype correlations in BSS. Results: In a comparison of whole exome sequencing data from the Hungarian and Anglo-Saxon BSS patients, we have identified three putative phenotype-modifying genetic variants: the rs1053023 SNP of the signal transducer and activator of transcription 3 (STAT3) gene, the rs1131877 SNP of the tumor necrosis factor receptor-associated factor 3 (TRAF3) gene and the rs202122812 SNP of the neighbor of BRCA1 gene 1 (NBR1) gene. Conclusions: Our study contributes to the accumulating evidence for the clinical importance of phenotype-modifying genetic factors, which are potentially important for the elucidation of genotype–phenotype correlations and disease prognosis.