Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Eur Acad Dermatol Venereol. 2023 Feb;37(2):411-419. doi: 10.1111/jdv.18692. Epub 2022 Nov 5.
Epidermolysis bullosa (EB) is a heterogeneous group of rare and incurable genetic blistering disorders.
The objective was to analyse the genotype-phenotype correlation in EB among Chinese individuals.
Next-generation sequencing and Sanger sequencing were performed to genetically confirm clinically diagnosed EB. Reverse transcription-PCR and splice-site analysis were used to evaluate the consequences of splicing mutations.
A total of 441 cases (413 families) across 11 genes were included. EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler EB, simplex and junctional compound EB accounted for 23.4%, 12.7%, 61.5%, 1.1% and 0.2%, respectively. In 16 probands with presumptive recessive EB, failed to find the second allele, COL7A1 (10), COL17A1 (4), LAMB3 (1) and ITGB4 (1). De novo mutations are common in dominant EB (63.8% in EBS, 27.5% in DEB) but extremely rare in recessive DEB (RDEB; 0.74%). Mosaicism is more common than presumed, with 5.4% of dominant EBS. In JEB, only 45.0% of patients with biallelic premature termination codon (PTC) mutations in laminin 332 genes died within 24 months, with a longer average survival age of 11.1 months. In JEB, unusual phenotypes are frequently observed, notably urinary tract involvement, duodenal atresia and EB nevi. In RDEB, 48.8% of cases with biallelic PTC mutations in COL7A1 exhibited a relatively mild phenotype; they are likely to develop a severe phenotype at 0-4 years old, and the PTC mutations position closer to the N-terminal, leading to earlier onset. Glycine substitution mutations in DEB have complex genotypic and phenotypic heterogeneity. The rare subtype, dominant and recessive compound DEB, consists of 1.8% of the total DEB.
This study reveals the general rules governing genotype-phenotype correlations, rare phenotypes and complex genotypes. Collectively, mutation analysis in different forms of EB provides the basis for improved subclassification with accurate genetic counselling and for prenatal diagnosis.
大疱性表皮松解症（EB）是一组罕见的、无法治愈的遗传性水疱性遗传疾病。
分析中国人群 EB 的基因型-表型相关性。
对临床诊断为 EB 的患者进行下一代测序和 Sanger 测序以进行基因确认。使用逆转录-PCR 和剪接位点分析来评估剪接突变的后果。
共纳入 11 个基因的 441 例（413 个家系）患者。单纯型 EB（EBS）、交界型 EB（JEB）、营养不良型 EB（DEB）、Kindler 型 EB、单纯型和交界型复合 EB 分别占 23.4%、12.7%、61.5%、1.1%和 0.2%。在 16 例推定的隐性 EB 先证者中，未能找到第二个等位基因，COL7A1（10）、COL17A1（4）、LAMB3（1）和 ITGB4（1）。显性 EB 中常发生新生突变（EBS 中 63.8%，DEB 中 27.5%），但隐性 DEB（RDEB；0.74%）中极为罕见。嵌合体比预期更为常见，显性 EBS 中有 5.4%。在 JEB 中，只有 45.0%携带双等位基因提前终止密码子（PTC）突变的 laminin 332 基因突变的患者在 24 个月内死亡，平均存活年龄为 11.1 个月。在 JEB 中，常观察到不寻常的表型，特别是泌尿道受累、十二指肠闭锁和 EB 痣。在 RDEB 中，48.8%携带双等位基因 PTC 突变的 COL7A1 患者表现出相对较轻的表型；他们可能在 0-4 岁时发展为严重表型，并且 PTC 突变位置更接近 N 端，导致发病更早。DEB 中的甘氨酸取代突变具有复杂的基因型和表型异质性。罕见的亚型，显性和隐性复合 DEB，占总 DEB 的 1.8%。
本研究揭示了基因型-表型相关性、罕见表型和复杂基因型的一般规律。不同形式的 EB 的突变分析为改进亚分类提供了依据，可进行准确的遗传咨询和产前诊断。
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