230 Early frameshift mutation in KRT14 cause a heterogeneous phenotype in a family with Naegeli-Franceschetti-Jadassohn syndrome

Abstract

Naegeli-Franceschetti-Jadassohn syndrome (NFJS) is a rare autosomal dominantly inherited genodermatosis. Only seven families with NFJS are currently reported in literature. Mutations in keratin 14 (KRT14) additionally cause dermatopathia pigmentosa reticularis (DPR), a phenotypically similar disease, as well as epidermolysis bullosa simplex (EBS). Our study aimed on identification of the causative mutation in an unknown family with NFJS and gain of knowledge on genotype-phenotype correlation in KRT14. We examined a five generation family with NFJS phenotype in eight individuals. Initially, the index patient visited our clinic because of difficulties in registration of her fingerprints. Since birth she has suffered from anhidrosis and palmoplantar keratoderma. Additionally, she had had patchy hyperpigmentations which disappeared over time. Clinical investigations on further family members revealed a heterogeneous severity of phenotype in the affected family members. We isolated gDNA from patients' lymphocytes and performed Sanger sequencing of exon 1 of KRT14. By that we identified a two base pair insertion leading to a frameshift and a premature stop codon after 10 amino acids. The same mutation, which is unknown in large databases like gnomAD (123,136 exome and 15,496 whole-genome sequences), has been found in further affected family members. The correlation between the genotype and phenotype in patients with KRT14 mutation is not completely understood. We present clinical and sequence data from this family and discuss them in context of the original NFJS family as well as other descriptions in literature.