{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:30:58Z","timestamp":1793313058933,"version":"4.5.0"},"reference-count":43,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Dermatol"],"published-print":{"date-parts":[[2026,3,1]]},"abstract":"\n Importance<\/jats:title>\n \n Recessive dystrophic epidermolysis bullosa (RDEB) is a rare monogenic blistering disorder with wide clinical heterogeneity, ranging from localized skin fragility to life-limiting systemic complications. Understanding genotype-phenotype correlations in\n COL7A1<\/jats:italic>\n , the causative gene, is critical for clinical prognostication, genetic counseling, and the rational design of emerging molecular therapies.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To determine the frequency of genotypic and phenotypic subtypes, and to assess whether variant type or location can predict phenotypic severity and extracutaneous complications in patients with RDEB carrying homozygous variants.<\/jats:p>\n <\/jats:sec>\n \n Evidence Review<\/jats:title>\n \n This was a systematic review of all RDEB genotypes and phenotypes reported to the International Dystrophic Epidermolysis Bullosa Patient Registry (DEB Registry) and eligible studies published in English from May 1993 to September 2025. PubMed, Cochrane Library, and Web of Science were searched and eligible studies were reviewed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020) guidelines. Included studies reported bi-allelic\n COL7A1<\/jats:italic>\n variants and clinical phenotypes. Data from the DEB Registry were cross-checked to supplement the published cases. Descriptive statistics were used for data analyses, and Fisher exact and \u03c7\n 2<\/jats:sup>\n methods were used to test additional genotype-phenotype correlations in patients with RDEB carrying homozygous variants.\n <\/jats:p>\n <\/jats:sec>\n \n Findings<\/jats:title>\n \n A total of 1802 patients with RDEB comprising 1002 pathogenic variants within\n COL7A1<\/jats:italic>\n were identified from 217 articles. Among the 706 patients with homozygous variants (mean [SD; range] age, 12.2 [13.0; 0-72] years), 533 (75.5%) had severe RDEB, most frequently associated with frameshift and nonsense variants (388 [72.8%] premature termination codons [PTCs]). In contrast, intermediate and milder subtypes were associated with missense or non-PTC variants. Variant location also influenced phenotype: homozygous variants affecting the noncollagenous 1 domain were associated with severe RDEB in 74 of 83 unique variants (89.2%). Extracutaneous involvement clustered in homozygous PTC carriers and was observed almost exclusively in severe RDEB, with occasional cases in the intermediate subtype and rare instances in the inversa, localized, and self-improving subtypes. Recurrent and population-specific variants suggested founder effects. Splice site and missense variants showed phenotypic variability, with augmented intelligence\u2212based predictions correlating with severity.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n In this systematic review, the type and site of pathogenic variants in\n COL7A1<\/jats:italic>\n correlated with the severity of RDEB phenotype across different nationalities, races, and ethnicities. These findings may provide improved patient prognosis, genetic counseling, and personalized therapeutics.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamadermatol.2025.5723","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T16:30:37Z","timestamp":1770222637000},"page":"292","source":"Crossref","is-referenced-by-count":3,"title":["Genotype-Phenotype Correlations in Recessive Dystrophic Epidermolysis Bullosa"],"prefix":"10.1001","volume":"162","author":[{"given":"Cara","family":"Heppell","sequence":"first","affiliation":[{"name":"Guy\u2019s, King\u2019s and St Thomas\u2019 School of Medicine, Faculty of Life Sciences & Medicine, King\u2019s College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping-Chen","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aim\u00e9e","family":"Longmore","sequence":"additional","affiliation":[{"name":"Guy\u2019s, King\u2019s and St Thomas\u2019 School of Medicine, Faculty of Life Sciences & Medicine, King\u2019s College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Shafik","sequence":"additional","affiliation":[{"name":"Guy\u2019s, King\u2019s and St Thomas\u2019 School of Medicine, Faculty of Life Sciences & Medicine, King\u2019s College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Ali","sequence":"additional","affiliation":[{"name":"Guy\u2019s, King\u2019s and St Thomas\u2019 School of Medicine, Faculty of Life Sciences & Medicine, King\u2019s College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavita S.","family":"Subramaniam","sequence":"additional","affiliation":[{"name":"Translational Research Office, University of Oxford, Oxford, United Kingdom"},{"name":"St John\u2019s Institute of Dermatology, School of Basic and Medical Biosciences, King\u2019s College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Antoniou","sequence":"additional","affiliation":[{"name":"Gene Expression and Therapy Group, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, King\u2019s College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Kai","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jemima E.","family":"Mellerio","sequence":"additional","affiliation":[{"name":"St John\u2019s Institute of Dermatology, School of Basic and Medical Biosciences, King\u2019s College London, London, United Kingdom"},{"name":"St John\u2019s Institute of Dermatology, Guy\u2019s and St Thomas\u2019 National Health Service Foundation Trust, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"McGrath","sequence":"additional","affiliation":[{"name":"Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan"},{"name":"St John\u2019s Institute of Dermatology, School of Basic and Medical Biosciences, King\u2019s College London, London, United Kingdom"},{"name":"St John\u2019s Institute of Dermatology, Guy\u2019s and St Thomas\u2019 National Health Service Foundation Trust, London, United Kingdom"},{"name":"Department of Molecular Genetics, King\u2019s College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su M.","family":"Lwin","sequence":"additional","affiliation":[{"name":"St John\u2019s Institute of Dermatology, School of Basic and Medical Biosciences, King\u2019s College London, London, United Kingdom"},{"name":"St John\u2019s Institute of Dermatology, Guy\u2019s and St Thomas\u2019 National Health Service Foundation Trust, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"4","key":"drv250007r1","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/bjd.18921","article-title":"Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.","volume":"183","author":"Has","year":"2020","journal-title":"Br J Dermatol"},{"issue":"3","key":"drv250007r2","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/S0888-7543(05)80204-6","article-title":"PCR-based detection of two exonic polymorphisms in the human type VII collagen gene (COL7A1) at 3p21.1.","volume":"14","author":"Christiano","year":"1992","journal-title":"Genomics"},{"issue":"7","key":"drv250007r3","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1111\/j.1600-0625.2008.00723.x","article-title":"Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosa.","volume":"17","author":"Dang","year":"2008","journal-title":"Exp Dermatol"},{"issue":"3","key":"drv250007r4","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1136\/jmg.2006.045302","article-title":"Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes.","volume":"44","author":"Varki","year":"2007","journal-title":"J Med Genet"},{"issue":"5","key":"drv250007r5","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1002\/(SICI)1098-1004(1997)10:5<408::AID-HUMU12>3.0.CO;2-3","article-title":"Strategy for identification of sequence variants in COL7A1 and a novel 2-bp deletion mutation in recessive dystrophic epidermolysis bullosa.","volume":"10","author":"Christiano","year":"1997","journal-title":"Hum Mutat"},{"issue":"2","key":"drv250007r6","first-page":"289","article-title":"Recurrent nonsense mutations within the type VII collagen gene in patients with severe recessive dystrophic epidermolysis bullosa.","volume":"55","author":"Hovnanian","year":"1994","journal-title":"Am J Hum Genet"},{"issue":"32","key":"drv250007r7","doi-asserted-by":"crossref","first-page":"20256","DOI":"10.1016\/S0021-9258(17)31984-1","article-title":"Cloning of human type VII collagen. Complete primary sequence of the alpha 1(VII) chain and identification of intragenic polymorphisms.","volume":"269","author":"Christiano","year":"1994","journal-title":"J Biol Chem"},{"issue":"6","key":"drv250007r8","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1007\/s40257-021-00626-3","article-title":"Investigational treatments for epidermolysis bullosa.","volume":"22","author":"Hou","year":"2021","journal-title":"Am J Clin Dermatol"},{"key":"drv250007r9","doi-asserted-by":"crossref","first-page":"455","DOI":"10.2147\/TCRM.S386923","article-title":"Innovations in the treatment of dystrophic epidermolysis bullosa (DEB): current landscape and prospects.","volume":"19","author":"Hou","year":"2023","journal-title":"Ther Clin Risk Manag"},{"issue":"5","key":"drv250007r10","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1093\/bjd\/ljaf015","article-title":"Functional genotype classification groups distinguish disease severity in recessive dystrophic epidermolysis bullosa.","volume":"192","author":"Pathmarajah","year":"2025","journal-title":"Br J Dermatol"},{"issue":"3","key":"drv250007r11","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.jaad.2024.04.073","article-title":"Functional genotype-phenotype associations in recessive dystrophic epidermolysis bullosa.","volume":"91","author":"So","year":"2024","journal-title":"J Am Acad Dermatol"},{"issue":"8","key":"drv250007r12","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0289558","article-title":"Clinical and allelic heterogeneity in dystrophic epidermolysis bullosa- lessons from an Indian cohort.","volume":"18","author":"Gupta","year":"2023","journal-title":"PLoS One"},{"key":"drv250007r13","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s12863-015-0211-2","article-title":"Assessing the quality of published genetic association studies in meta-analyses: the quality of genetic studies (Q-Genie) 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China.","volume":"37","author":"Chen","year":"2023","journal-title":"J Eur Acad Dermatol Venereol"},{"issue":"3","key":"drv250007r25","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1074\/jbc.M108779200","article-title":"The recombinant expression of full-length type VII collagen and characterization of molecular mechanisms underlying dystrophic epidermolysis bullosa.","volume":"277","author":"Chen","year":"2002","journal-title":"J Biol Chem"},{"issue":"4","key":"drv250007r26","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1111\/ced.12809","article-title":"Recessive dystrophic epidermolysis bullosa caused by a de novo interstitial deletion spanning COL7A1 and a hemizygous splicing mutation in trans.","volume":"41","author":"Lee","year":"2016","journal-title":"Clin Exp Dermatol"},{"issue":"3","key":"drv250007r27","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1111\/1523-1747.ep12336276","article-title":"Premature termination codon mutations in the type VII collagen gene in recessive dystrophic epidermolysis bullosa result in nonsense-mediated mRNA decay and absence of functional protein.","volume":"109","author":"Christiano","year":"1997","journal-title":"J Invest Dermatol"},{"issue":"3","key":"drv250007r28","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1083\/jcb.138.3.719","article-title":"Laminin 5 binds the NC-1 domain of type VII collagen.","volume":"138","author":"Rousselle","year":"1997","journal-title":"J Cell Biol"},{"issue":"3","key":"drv250007r29","doi-asserted-by":"crossref","DOI":"10.1111\/exd.15042","article-title":"Stop codon readthrough as a treatment option for epidermolysis bullosa-where we are and where we are going.","volume":"33","author":"Zandanell","year":"2024","journal-title":"Exp Dermatol"},{"issue":"1","key":"drv250007r30","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s13023-016-0489-9","article-title":"Inherited epidermolysis bullosa and squamous cell carcinoma: a systematic review of 117 cases.","volume":"11","author":"Montaudi\u00e9","year":"2016","journal-title":"Orphanet J Rare Dis"},{"issue":"8","key":"drv250007r31","doi-asserted-by":"crossref","DOI":"10.2340\/00015555-3875","article-title":"Cutaneous squamous cell carcinoma in epidermolysis bullosa: a 28-year retrospective study.","volume":"101","author":"Robertson","year":"2021","journal-title":"Acta Derm Venereol"},{"issue":"2","key":"drv250007r32","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jaad.2008.09.035","article-title":"Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006.","volume":"60","author":"Fine","year":"2009","journal-title":"J Am Acad Dermatol"},{"key":"drv250007r33","doi-asserted-by":"crossref","DOI":"10.1111\/odi.70114","article-title":"Oral manifestations in different subtypes of hereditary epidermolysis bullosa: a retrospective case series from an Asian cohort.","author":"Li","year":"2025","journal-title":"Oral Dis"},{"issue":"5","key":"drv250007r34","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1016\/j.ajpath.2012.07.018","article-title":"Type VII collagen deficiency causes defective tooth enamel formation due to poor differentiation of ameloblasts.","volume":"181","author":"Umemoto","year":"2012","journal-title":"Am J Pathol"},{"issue":"22","key":"drv250007r35","doi-asserted-by":"crossref","first-page":"12222","DOI":"10.3390\/ijms222212222","article-title":"Therapeutic prospects of exon skipping for epidermolysis bullosa.","volume":"22","author":"Vermeer","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"3","key":"drv250007r36","doi-asserted-by":"crossref","DOI":"10.1016\/j.xjidi.2023.100191","article-title":"Cytosine deaminase base editing to restore COL7A1 in dystrophic epidermolysis bullosa human: murine skin model.","volume":"3","author":"Naso","year":"2023","journal-title":"JID 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polymorphism in the matrix metalloproteinase-1 gene promoter.","volume":"89","author":"Almaani","year":"2009","journal-title":"Acta Derm Venereol"},{"issue":"3","key":"drv250007r43","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.jdermsci.2006.01.005","article-title":"Single cell PCR amplification of microsatellites flanking the COL7A1 gene and suitability for preimplantation genetic diagnosis of Hallopeau-Siemens recessive dystrophic epidermolysis bullosa.","volume":"42","author":"Fassihi","year":"2006","journal-title":"J Dermatol Sci"}],"container-title":["JAMA 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