Functional genotype classification groups distinguish disease severity in recessive dystrophic epidermolysis bullosa

Abstract Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic disorder due to pathogenic variants in the COL7A1 gene. In this study we determined the association between different categories of COL7A1 variants and clinical disease severity in 236 RDEB patients in North America. Published reports or in-silico predictions were used to assess the impact of pathogenic variants in COL7A1 on type VII collagen (C7) protein function. Three impact categories were postulated: genotypes that would likely cause a low impact on C7 function (splice B/missense, missense/missense), medium impact [premature termination codon (PTC)/splice B, splice A/splice B, PTC/missense, splice A/missense, splice B/splice B] and high impact (PTC/PTC, PTC/splice A, splice A/splice A). Splice A variants are predicted to cause downstream PTCs while splice B variants cause in-frame exon skipping and are therefore less deleterious. Severity of functional impact was significantly associated with history of gastrostomy tube placement, esophageal dilation, hand surgery, anemia, renal disease, chronic wounds, diffuse skin involvement and history of squamous cell carcinoma. Odds of death were 3.25 (1.24-8.50, p=0.02) higher in the high vs medium impact group. High impact group patients had worse clinical outcomes. Functional genotype categories are a feasible approach to risk stratify patients based on predicted C7 function.