Recessive dystrophic epidermolysis bullosa subtypes linked to type VII protein function

Key takeaways:

• The impact level of the variant on type VII collagen protein expression was linked to disease severity.
• High-impact variants were more associated with severe disease than medium- and low-impact variants.

Based on a variant’s impact on type VII collagen protein function, patients with recessive dystrophic epidermolysis bullosa can be categorized into clinically meaningful subgroups to better guide disease management, according to a study.

“Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genodermatosis caused by pathogenic variants in the COL7A1 gene, which encodes for type VII collagen (C7) protein,” Jodi Y. So, MD, a resident in the department of dermatology at Stanford University, and colleagues wrote. “C7 is the primary component of anchoring fibrils (AFs), extracellular superstructures which maintain dermal-epidermal adhesion and structural integrity.”

According to So and colleagues, previous studies have demonstrated that the impact on C7 in patients with RDEB may dictate disease severity. Therefore, in their current study, the researchers set out to characterize the relative severity of lesser-known genotypes on patients with RDEB based on the impact on C7’s function.

The study included 83 participants (mean age, 24.1 years; 57.8% male; 48.2% non-Hispanic white) with RDEB. Patients were categorized by their RDEB type which was measured by the degree of variant impact on C7 expression and function. Most patients (63.9%) had high-impact variants, whereas the remaining had either medium-impact (25.3%) or low-impact variants (10.8%).

Results showed that the impact level of the variant on C7 expression was associated with clinical severity. High-impact variants were associated with worse RDEB subtype and clinical disease, with 90.4% of patients with high-impact variants reporting an increased prevalence of generalized blistering vs. 72.7% and 55.6% of patients with medium-impact and low-impact variants, respectively (P = .002).

Those with high-impact variants were also more likely to be diagnosed with severe RDEB compared with those with medium- or low-impact variants (71.2% vs. 22.7% and 11.1%, respectively; P < .001).

Overall, the researchers found that patients with high-impact variants had significantly worse outcomes. According to age-adjusted regressions, patients with high-impact variants had 40.8-fold greater odds of developing squamous cell carcinoma vs. patients with low-impact variants (P = .02). The incidence of death was also much higher among patients with high-impact variants vs. those with medium- or low-impact variants (30.8% vs. 9.1% and 0%; P = .04).

“Our results demonstrate that a simplified, functional pathogenic variant classification framework based on C7 function and expression can categorize RDEB patients into clinically meaningful subgroups that can guide patient prognostication and counseling,” the authors concluded.