The British journal of dermatology · 2025
Functional genotype classification groups distinguish disease severity in recessive dystrophic epidermolysis bullosa.
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Pathmarajah Pirunthan, Eid Edward, Nazaroff Jaron, So Jodi, Mittal Vaishali, Harris Nicki, Li Shufeng, Lucky Anne W, Gorell Emily S, Peoples Kathleen G, Pope Elena, Lara-Corrales Irene, Paller Amy S, Wiss Karen, Perman Marissa J, Eichenfield Lawrence F, Levy Moise L, Morel Kimberly D, García-Romero Maria T, McCuaig Catherine C, Saber Melissa, Marinkovich M Peter, Oro Anthony, Bruckner Anna L, Tang Jean Y
Аннотация
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.
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.