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
Department of Dermatology, Stanford University School of Medicine, Stanford, California.
CSIR-Institute of Genomics & Integrative Biology, Academy of Scientific and Innovative Research, New Delhi, India.
J Am Acad Dermatol. 2024 Sep;91(3):448-456. doi: 10.1016/j.jaad.2024.04.073. Epub 2024 May 11.
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.
隐性营养不良型大疱性表皮松解症（RDEB）的基因型-表型关联一直难以阐明。
研究RDEB的基因型-表型关联，并探索一种基于功能的基因型分类方法。
对RDEB患者进行临床检查和基因检测，包括根据RDEB亚型和水疱形成程度评估临床疾病。根据每个变体对VII型胶原蛋白功能的影响，参照最新文献对基因型进行评估，随后根据对VII型胶原蛋白功能的影响程度分为低影响（剪接/错义、错义/错义）、中等影响（过早终止密码子[PTC]/错义、剪接/剪接）和高影响（PTC/PTC、PTC/剪接）。使用Kruskal-Wallis检验、Fisher精确检验和年龄调整回归分析研究基因型-表型关联。
纳入83名参与者。高影响变体与更严重的RDEB亚型和临床疾病相关，包括全身水疱形成的患病率增加（低影响变体为55.6%，中等影响变体为72.7%，高影响变体为90.4%，P = 0.002）。在年龄调整回归分析中，与低影响变体相比，携带高影响变体的参与者患鳞状细胞癌的几率高40.8倍（P = 0.02），与中等影响变体相比，死亡几率高5.7倍（P = 0.05）。
横断面设计。
基于功能的基因型分类可能有助于分层RDEB的严重程度；高影响变体与更差的临床结果相关。需要在更大的队列中进行进一步验证。
