Functional Genotype-Phenotype Associations in Recessive Dystrophic Epidermolysis Bullosa

Jodi Y So; Jaron Nazaroff; Vamsi K Yenamandra; Emily S Gorell; Nicki Harris; Shivali Fulchand; Edward Eid; John A Dolorito; M Peter Marinkovich; Jean Y Tang

doi:10.1016/j.jaad.2024.04.073

Functional Genotype-Phenotype Associations in Recessive Dystrophic Epidermolysis Bullosa

J Am Acad Dermatol. 2024 May 10:S0190-9622(24)00732-1. doi: 10.1016/j.jaad.2024.04.073. Online ahead of print.

Authors

Affiliations

¹ Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
² CSIR-Institute of Genomics & Integrative Biology, Academy of Scientific and Innovative Research, New Delhi, India.
³ Division of Dermatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁴ Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA; Dermatology Service, Veterans Affairs Palo Alto Medical Center, Palo Alto, CA, USA.
⁵ Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: tangy@stanford.edu.

PMID: 38735484
DOI: 10.1016/j.jaad.2024.04.073

Abstract

Background: Genotype-phenotype associations in recessive dystrophic epidermolysis bullosa (RDEB) have been difficult to elucidate.

Objective: To investigate RDEB genotype-phenotype associations and explore a functional approach to genotype classification.

Methods: 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 (C7) function per updated literature, and subsequently categorized by degree of impact on C7 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.

Results: 83 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=0.002). 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=0.02), and 5.7-fold greater odds of death compared to medium-impact variants (p=0.05).

Limitations: Cross-sectional design.

Conclusion: Functional genotype categories may stratify RDEB severity; high-impact variants correlated with worse clinical outcomes. Further validation in larger cohorts is needed.

Keywords: epidermolysis bullosa; genetic diseases; genodermatoses; genotype-phenotype associations; recessive dystrophic epidermolysis bullosa.