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. 2025 Apr 28;192(5):917-925.
doi: 10.1093/bjd/ljaf015.

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

Pirunthan Pathmarajah  1 , Edward Eid  1 , Jaron Nazaroff  1 , Jodi So  1 , Vaishali Mittal  1 , Nicki Harris  1 , Shufeng Li  1 , Anne W Lucky, Emily S Gorell, Kathleen G Peoples, Elena Pope, Irene Lara-Corrales, Amy S Paller, Karen Wiss, Marissa J Perman, Lawrence F Eichenfield, Moise L Levy, Kimberly D Morel, Maria T García-Romero, Catherine C McCuaig, Melissa Saber, M Peter Marinkovich  1 , Anthony Oro  1 , Anna L Bruckner, Jean Y Tang  1
Affiliations

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

Pirunthan Pathmarajah et al. Br J Dermatol. .

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.

Plain language summary

Epidermolysis bullosa (‘EB’ for short) is a group of rare inherited conditions that cause the skin to blister easily. A type of EB known as ‘recessive dystrophic EB’ (or ‘RDEB’ for short) is caused by changes in a gene called ‘COL7A1’. Much of the skin is covered in blisters at birth or shortly afterwards. There is also extensive blistering on the inside of the body. The exact number of people with EB is unclear. However, estimates suggest that 25,000 to 50,000 people in the USA have EB. Less than five percent of all cases of EB are classified as RDEB. In this study, we looked at how different changes in the COL7A1 gene affect how severe the disease is in 236 patients with RDEB in North America. We used information from other studies or computer predictions to see how these genetic changes affect a protein called ‘type VII collagen’ (‘C7’ for short). We divided these genetic changes into three groups based on how much they affect C7: low-impact, medium-impact and high-impact. Patients in the high-impact group were more likely to have more severe complications like needing a tube for feeding, surgery on the hands or other health issues. They also had a higher chance of dying and a history of a serious type of skin cancer called squamous cell carcinoma. By understanding how these genetic changes affect proteins and by categorizing patients into different groups, doctors can better understand and predict how severe RDEB might be for each patient.

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Conflict of interest statement

Conflicts of interest: J.Y.T. is an investigator for clinical trials sponsored by Abeona Therapeutics and a consultant for Sol-Gel. M.P.M. is an investigator for clinical trials sponsored by Abeona Therapeutics, Castle Creek Biosciences, RHEACELL, ANTEROGEN, argenx and Cabaletta. A.L.B. is an investigator for clinical trials sponsored by RHEACELL, and has been a consultant for Amryt, Krystal Bio and Abeona Therapeutics. A.S.P. is an investigator for AbbVie, Applied Pharma Research, Dermavant, Eli Lilly, Incyte, Janssen, Krystal, Regeneron and UCB; a consultant for Aegerion Pharma, Azitra, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Johnson & Johnson, Krystal, LEO Pharma, Novartis, Primus, Regeneron, Sanofi Genzyme, SEANERGY, TWI Biotechnology and UCB; and is on the data safety monitoring board for AbbVie, Abeona, Catawba, Galderma and InMed. E.S.G. has been a consultant for Abeona Therapeutics, Amryt and Krystal Bio. C.C.M. has been a consultant for AbbVie, Bausch, Boehringer, Galderma, Incyte, J&J, Eli Lilly, LEO Pharma, Novartis, L’Oréal, Pfizer, Sanofi and Sun Pharma. M.J.P. has been a consultant for Abeona and is an investigator for a clinical trial sponsored by Aegle Therapeutics. I.L.-C. has been a consultant for Sanofi Genzyme, Abeona, Avicanna, Ipsen, Novartis, Eli Lilly and UCB; a speaker for Sanofi Genzyme, AbbVie and Eli Lilly; and has received grants or been an investigator for AbbVie, Clementia, Eli Lilly, Timber, Arcutis, La Roche Posay, Sanofi Genzyme, Regeneron, Mayne Pharma and Bristol Myers Squibb. She is also a board member of DeBRA Canada, Camp Liberté and Children International Summer Villages. M.L.L. is a consultant for Abeona (Strategic Council/Advisory Board), Amgen (DMC Chair, 2023), Arcutis (Advisory Board, 2023/4), Castle Creek (Advisory Board), Krystal Biotech (Advisory Board) and DUSA Pharmaceuticals (Advisory Board, 2021); an investigator for Castle Creek, Janssen, Krystal Biotech and Rheacell; a member of the data safety monitoring board for Mayne Pharma (2020/21) and Novan (2019, 2022); an advisor for Novan (2022); and a section editor and author for UpToDate. K.W. is an investigator for clinical trials sponsored by Abeona Therapeutics. L.F.E. is an advisor or consultant for Almirall Hermal, Anacor Pharmaceuticals, Cutanea Life Sciences, Dermavant Sciences, Dermira, DS Biopharma, Eli Lilly, Forte, Galderma Laboratories, Incyte, LEO Pharma, L’Oréal, MatriSys, Medimetriks Pharmaceuticals, MorphoSys, Novan, Novartis Pharmaceuticals, Ortho Dermatologics, Otsuka Pharmaceutical, Pfizer, Regeneron Pharmaceuticals and Sanofi Genzyme; has been a speaker or a member of a speakers’ bureau for Ortho Dermatologics, Valeant Pharmaceuticals, Asana Biosciences and Glenmark; and has been an investigator for AbbVie, LEO Pharma, Regeneron Pharmaceuticals and Sanofi Genzyme. E.P. declares a conflict of interest regarding intellectual property of the iscorEB instrument. K.D.M. has no direct conflicts of interest, but her spouse is an independent director of Belite Bio and receives salary support. A.W.L. has been an investigator for Krystal Pharma and Phoenicis. M.T.G.-R. has been a speaker for Carnot Panalab and L’Oréal; has received honoraria for academic activities for Carnot Panalab, Chiesi and Pierre Fabre; and has received grants from Pierre Fabre. The other authors declare no conflicts of interest.

Comment in

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