307 Homozygous Biallelic KRT5 Mutations in Epidermolysis Bullosa Simplex, Including a Complete Human Keratin 5 “Knock-Out”, in Families with Extensive Consanguinity (original) (raw)

2019, Journal of Investigative Dermatology

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 gene (CYLD). Concerning the so far reported phenotypes and the underlying CYLD mutations, it is difficult to establish genotype-phenotype correlations in BSS. We have recently investigated a Hungarian family (with Bukovinian origin) and an Anglo-Saxon BSS pedigree, in whom the affected family members-despite of carrying the same diseasecausing mutation (c.2806C>T, p.Arg936X) of the CYLD gene-show striking differences in their phenotypes. The aim of our study was to identify phenotype modifier genetic factors, which could help the understanding of genotype-phenotype correlations in BSS. Comparing the WES data of the Hungarian and Anglo-Saxon BSS patients, here 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. Our study contributes to the accumulating evidence describing the clinical importance of genetic phenotype modifying factors, which have high potential in the elucidation of genotype-phenotype correlations and disease prognosis.

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