Epidermolytic Hyperkeratosis via the KRT1 Gene

Epidermolytic hyperkeratosis (also called bullous congenital ichthyosiform erythroderma) is a keratinization disorder characterized by erythema, epidermal blisters at birth, and progressive hyperkeratosis (thickening of the cornified layer of the skin). The prevalence is 1 in 100,000 to 300,000 newborns (Yang et al. 1996).

KRT1-related epidermolytic hyperkeratosis is usually inherited in an autosomal dominant manner. In addition, defects in KRT1 also cause other autosomal dominant conditions: Palmoplantar keratoderma, Ichthyosis, cyclic, with epidermolytic hyperkeratosis and Ichthyosis histrix, Curth-Macklin type. In the epidermis of the skin, keratin 1 protein partners with keratin 10 protein to form keratin intermediate filaments in the suprabasal layer of the epidermis (Blanpain and Fuchs 2009). To date, more than 50 unique pathogenic variants have been documented in in KRT1 (Human Gene Mutation Database). They include: missense (70%), splicing (~9%), small deletions and insertions (~20%), and 1 complex rearrangement involving KRT1. De novo pathogenic variants were seen in ~50% of reported cases. A recurrent pathogenic variant is c.1436T>C, p.Ile479Thr (HGMD; Virtanen et al. 2001; Arin et al. 2011).

KRT1 and KRT10 pathogenic variants were identified in 9 and 19 of 28 studied unrelated patients (Arin et al. 2011).

Only 1 complex rearrangement involving KRT1 has been reported (Virtanen et al. 2001).

This test provides full coverage of all coding exons of the KRT1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).