Abstract
BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic disorder caused by pathogenic variants in COL7A1. OBJECTIVES: To determine the association between different COL7A1 variants and clinical disease severity in 236 North American patients with RDEB. METHODS: 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 be likely to cause a low impact on C7 function (splice B/missense, missense/missense); a medium impact [premature termination codon (PTC)/splice B, splice A/splice B, PTC/missense, splice A/missense, splice B/splice B]; and a 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. RESULTS: The severity of functional impact was significantly associated with a history of gastrostomy tube placement, oesophageal dilation, hand surgery, anaemia, renal disease, chronic wounds, diffuse skin involvement and a history of squamous cell carcinoma. The odds of death were 3.5 time higher in the high-impact vs. medium-impact group (95% confidence interval 1.24-8.50; P = 0.02). Patients in the high-impact group had worse clinical outcomes. CONCLUSIONS: Functional genotype categories are a feasible approach to risk-stratify patients based on predicted C7 function.