Functional genotype-phenotype associations in recessive dystrophic epidermolysis bullosa

• Published in: Journal of the American Academy of Dermatology Vol. 91; no. 3; pp. 448 - 456
• Main Authors: So, Jodi Y., Nazaroff, Jaron, Yenamandra, Vamsi K., Gorell, Emily S., Harris, Nicki, Fulchand, Shivali, Eid, Edward, Dolorito, John A., Marinkovich, M. Peter, Tang, Jean Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2024
• Subjects: Adolescent; Adult; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Child; Child, Preschool; Collagen Type VII - genetics; epidermolysis bullosa; Epidermolysis Bullosa Dystrophica - genetics; Epidermolysis Bullosa Dystrophica - pathology; Female; Genes, Recessive; Genetic Association Studies; genetic diseases; genodermatoses; Genotype; genotype-phenotype associations; Humans; Male; Middle Aged; Phenotype; recessive dystrophic epidermolysis bullosa; Severity of Illness Index; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Young Adult; genetic diseases; genotype-phenotype associations; epidermolysis bullosa; AF; genodermatoses; CI; RDEB; recessive dystrophic epidermolysis bullosa; pOR; SCC; C7; PTC; BMI
• ISSN: 0190-9622; 1097-6787; 1097-6787
• DOI: 10.1016/j.jaad.2024.04.073

Genotype-phenotype associations in recessive dystrophic epidermolysis bullosa (RDEB) have been difficult to elucidate. To investigate RDEB genotype-phenotype associations and explore a functional approach to genotype classification. Clinical examination and genetic testing of RDEB subjects, including assessment of clinical disease by RDEB subtype and extent of blistering. Genotypes were evaluated according to each variant's effect on type VII collagen function per updated literature and subsequently categorized by degree of impact on VII collagen function as low-impact (splice/missense, missense/missense), medium-impact (premature termination codon [PTC]/missense, splice/splice), and high-impact (PTC/PTC, PTC/splice). Genotype-phenotype associations were investigated using Kruskal-Wallis and Fisher's exact tests, and age-adjusted regressions. Eighty-three participants were included. High-impact variants were associated with worse RDEB subtype and clinical disease, including increased prevalence of generalized blistering (55.6% for low-impact vs 72.7% medium-impact vs 90.4% high-impact variants, P = .002). In age-adjusted regressions, participants with high-impact variants had 40.8-fold greater odds of squamous cell carcinoma compared to low-impact variants (P = .02), and 5.7-fold greater odds of death compared to medium-impact variants (P = .05). Cross-sectional design. Functional genotype categories may stratify RDEB severity; high-impact variants correlated with worse clinical outcomes. Further validation in larger cohorts is needed.