Dystrophia Smolandiensis is characterized by a novel NQO1 variant and a distinct phenotype from COL17A1-associated...

To determine the molecular cause of the two epithelial recurrent erosion dystrophies, Dystrophia Smolandiensis and Dystrophia Helsinglandica, and to identify phenotypic differences between the two conditions.

DNA samples and clinical data from structured interview records were obtained from the Swedish families in which Dystrophia Smolandiensis and Dystrophia Helsinglandica were originally characterized. Candidate variant detection was performed using combinations of linkage analysis, Sanger sequencing, exome sequencing and genome sequencing. Differences in age of onset and precipitating factors of erosive episodes were assessed using the Wilcoxon rank sum test and Fisher's exact test.

In Dystrophia Smolandiensis, the novel candidate variant NQO1 c.535 T>A p.(Phe179Ile) co-segregated with disease across 49 informative meioses. In Dystrophia Helsinglandica, the known pathogenic splice variant COL17A1 c.3156C>T was identified. There were significant phenotypic differences between the two conditions. The median age of onset was lower in Dystrophia Smolandiensis (2.5 years vs. 6 years, p = 0.00065). Cigarette smoke, intense sunlight and pregnancy were distinct precipitating factors of erosive episodes in Dystrophia Smolandiensis (p = 0.0010, p < 0.0001 and p = 0.016, respectively), whereas minor trauma to the eye was specific to Dystrophia Helsinglandica (p < 0.0001).

NQO1 is a candidate gene for Dystrophia Smolandiensis, while Dystrophia Helsinglandica is synonymous with COL17A1-associated ERED. The two conditions are characterized by distinct phenotypic differences. Based on these findings, we suggest a reclassification of epithelial recurrent erosion dystrophies guided by genetics. We propose designating COL17A1-associated epithelial recurrent erosion dystrophy as ERED1 and NQO1-associated epithelial recurrent erosion dystrophy as ERED2.