Novel mutations in Darier disease and association to self-reported disease severity

<div><p>Darier disease is a rare and severe autosomal dominant skin disease characterised by malodorous keratotic papules in seborrheic areas of the skin. Darier disease affects up to 1 in 30 000 people and is caused by mutations in the <i>ATP2A2</i> gene, which encodes to the sarco/endoplasmic reticulum calcium-ATPase isoform 2 that pumps calcium into the endoplasmic reticulum. Although many <i>ATP2A2</i> variants have been described, it is not known if genotype correlates with phenotype, which could be important for prognosis and treatment. This is the first study to use whole exome sequencing to screen the <i>ATP2A2</i> gene in a cohort of 28 clinically diagnosed Darier disease patients. Twenty-one different disease causing variants were identified and 15 of these were novel. Sixteen of the 21 variants were predicted to be pathogenic using <i>in silico</i> prediction programs. There were seven missense, four intronic/splice-sites, three frameshifts, two in-frame deletions, four nonsense and one synonymous mutations. This study also found ten patients who harbour more than one <i>ATP2A2</i> variant. The phenotype of the patient cohort was assessed by photography and by patient questionnaires. The genotype-phenotype association was examined for all variants in relation to the patient’s disease severity score, and no correlation could be established.</p></div

Medication effect (1–5), disease severity (mild–severe) and disease severity (1–5) scores sorted by mutation type.

<p>Medication effect and disease severity score (Top and bottom), a score of 1 = bad, 2 = acceptable, 3 = good, 4 = very good or 5 = excellent. Disease severity rate (Middle), a score of 1 = severe, 2 = moderate and 3 = mild. A score of 0 corresponds to patient’s lack of answer to a particular category. The type of <i>ATP2A2</i> mutation is shown on the x-axis, and they are sorted into seven categories: No mutations, benign, missense, in-frame deletion, splice-site, frameshift and nonsense mutations. ● represent patients receiving systemic treatment; ▲represents patients receiving topical treatment; ◆ represent patients receiving no treatment and represent patients who have received laser treatment. The different coloured points represent the patients with two <i>ATP2A2</i> variants. Points with the same colours are variants in the same patient.</p

Patient clinical characteristics.

<p>Patient clinical characteristics.</p