The phenotypic spectrum of genodermatoses is continuously expanding. Three individuals were referred because of a highly unusual phenotype comprising sparse brittle hair, dystrophic nails, palmoplantar keratoderma and trauma-induced skin blistering. Whole exome sequencing analysis identified a heterozygous large genomic alteration of ~116,0000 bp resulting in the deletion of the KRT9, KRT14, KRT15, KRT16, KRT19 genes as well as part of KRT17. This genomic change leads to the generation of a truncated KRT17 protein composed of the first 3 exons of the gene and part of intron 3. The three patients were found to carry the heterozygous genomic deletion while their healthy parents did not, suggestive of germline mosaicism. The genomic alteration was found to result in reduced KRT17 expression in patient skin. More importantly, the abnormal truncated KRT17 was found to exert a deleterious effect on keratinocyte cytoskeleton formation, leading to keratin aggregation. Co- expression of wildtype and truncated KRT17 proteins also caused keratin aggregation, indicative of the dominant negative effect of the deletion. In conclusion, we are reporting on a novel clinical phenotype that was found to result from germline mosaicism for a large genomic deletion spanning 6 keratin genes, thus expanding the spectrum of clinical manifestations associated with keratin dysfunction.

ESDR261 - A novel skin phenotype resulting from heterozygous deletion of six keratin genes

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