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

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic disorder caused by pathogenic variants in COL7A1. To determine the association between different COL7A1 variants and clinical disease severity in 236 North American patients with RDEB. 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. 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. Functional genotype categories are a feasible approach to risk-stratify patients based on predicted C7 function.