Pathmarajah Pirunthan, Eid Edward, Nazaroff Jaron, So Jodi, Mittal Vaishali, Harris Nicki, Li Shufeng, Lucky Anne W, Gorell Emily S, Peoples Kathleen G, Pope Elena, Lara-Corrales Irene, Paller Amy S, Wiss Karen, Perman Marissa J, Eichenfield Lawrence F, Levy Moise L, Morel Kimberly D, García-Romero Maria T, McCuaig Catherine C, Saber Melissa, Marinkovich M Peter, Oro Anthony, Bruckner Anna L, Tang Jean Y
Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
Br J Dermatol. 2025 Apr 28;192(5):917-925. doi: 10.1093/bjd/ljaf015.
Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic disorder caused by pathogenic variants in COL7A1.
To determine the association between different COL7A1 variants and clinical disease severity in 236 North American patients with RDEB.
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.
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.
Functional genotype categories are a feasible approach to risk-stratify patients based on predicted C7 function.
隐性营养不良型大疱性表皮松解症（RDEB）是一种由COL7A1基因致病性变异引起的遗传性疾病。
确定236例北美RDEB患者中不同COL7A1变异与临床疾病严重程度之间的关联。
使用已发表的报告或计算机预测来评估COL7A1基因致病性变异对VII型胶原蛋白（C7）蛋白功能的影响。假定了三种影响类别：可能对C7功能产生低影响的基因型（剪接B/错义、错义/错义）；中等影响[过早终止密码子（PTC）/剪接B、剪接A/剪接B、PTC/错义、剪接A/错义、剪接B/剪接B]；以及高影响（PTC/PTC、PTC/剪接A、剪接A/剪接A）。预测剪接A变异会导致下游PTC，而剪接B变异会导致框内外显子跳跃，因此危害较小。
功能影响的严重程度与胃造瘘管置入史、食管扩张、手部手术、贫血、肾脏疾病、慢性伤口、弥漫性皮肤受累及鳞状细胞癌病史显著相关。高影响组的死亡几率是中等影响组的3.5倍（95%置信区间1.24 - 8.50；P = 0.02）。高影响组患者的临床结局更差。
基于预测的C7功能，功能基因型类别是对患者进行风险分层的可行方法。
