确定导致大疱性表皮松解伴幽门闭锁的ITGB4基因中两个罕见和新的大缺失。

大疱性表皮松解伴幽门闭锁（EB-PA）是一种罕见的常染色体隐性遗传病，其预后从致命到非常轻微不等。EB-PA分为单纯型（EBS-PA:OMIM#612138）和连接型（JEB-PA:OMIM#226730），由ITGA6、ITGB4和PLEC基因突变引起。我们报告了6例EB-PA患者的分析，其中包括两对双卵双胞胎。进行皮肤免疫荧光表位定位，然后进行PCR和ITGB4基因直接测序。其中两名患者出现与错义ITGB4基因突变相关的非致死性EB-PA。对于其他四例，由于多种ITGB4新突变（2个大的缺失、1个剪接位点突变和3个错义突变），出生后早期死亡与β4整合素的完全缺乏有关。其中一个缺失跨越278 bp，是迄今为止报道的该基因最大的缺失之一。值得注意的是，我们还首次发现ITGB4基因中一个新突变的创始人效应。我们在ITGB4基因中发现了6个新的突变，将其添加到突变数据库中。我们的结果揭示了基因型-表型相关性，这有助于对这种异质性疾病的分子理解，这是预后的关键问题，也是EB治疗新的循证治疗选择的发展。

Epidermolysis bullosa with pyloric atresia (EB-PA) is a rare autosomal recessive hereditary disease with a variable prognosis from lethal to very mild. EB-PA is classified into Simplex form (EBS-PA: OMIM #612138) and Junctional form (JEB-PA: OMIM #226730), and it is caused by mutations in ITGA6, ITGB4 and PLEC genes. We report the analysis of six patients with EB-PA, including two dizygotic twins. Skin immunofluorescence epitope mapping was performed followed by PCR and direct sequencing of the ITGB4 gene. Two of the patients presented with non-lethal EB-PA associated with missense ITGB4 gene mutations. For the other four, early postnatal demise was associated with complete lack of β4 integrin due to a variety of ITGB4 novel mutations (2 large deletions, 1 splice-site mutation and 3 missense mutations). One of the deletions spanned 278 bp, being one of the largest reported to date for this gene. Remarkably, we also found for the first time a founder effect for one novel mutation in the ITGB4 gene. We have identified 6 novel mutations in the ITGB4 gene to be added to the mutation database. Our results reveal genotype-phenotype correlations that contribute to the molecular understanding of this heterogeneous disease, a pivotal issue for prognosis and for the development of novel evidence-based therapeutic options for EB management.