神经纤维瘤病I型(NF1)是一种最常见的常染色体显性疾病,因为估计发病率是3500例新生儿中的1例。在这项研究中,我们提出了两个新的剪接NF1变体的生物信息学和功能表征,在NF1患者中检测到。患者1,携带NF1:c.122A>T,它引入了一个新的外显子5供体剪接位点,被诊断为激素阳性,47岁的Her-2阴性乳腺癌。她对NF1进行了非典型的介绍,几乎没有咖啡色斑点,也没有Lisch结节。患者由于锁骨下动脉破裂而出现血胸,以前被描述为NF1的极为罕见的并发症。患者2,携带NF1:c.7395-17T>G,创建一个新的内含子3'受体剪接位点,有相当典型的NF1临床表现:她的舌头在她的左掌骨区域和左脚形成,骨盆里的丛状神经纤维瘤,几个咖啡馆-au-lait点,和腋窝雀斑.她还被诊断出患有认知障碍。在报告中,我们提出了两个新的变异体,它们根据NGS和mRNA分析被成功分类.根据mRNA分析的结果,根据ACMG指南,应用支持的证据类别PS3,PM2,PP3和PP1,两种变异均被分类为可能致病.通过表征这两个新的NF1剪接变体,我们已经在两个先证者中证实了神经纤维瘤病I型表型.
Neurofibromatosis type I (NF1) is one of the most common autosomal dominant disorders, since the estimated incidence is one in 3,500 births. In this study, we present bioinformatical and functional characterization of two novel splicing NF1 variants, detected in NF1 patients. Patient 1, carrying NF1:c.122A>T, which introduces a new exonic 5\' donor splice site, was diagnosed with hormone-positive, Her-2-negative breast cancer at the age of 47. She had an atypical presentation of NF1, with few café-au-lait spots and no Lisch nodules. Patient developed a hemothorax due to subclavian artery rupture, which has previously been described as an extremely rare complication of NF1. Patient 2, carrying NF1:c.7395-17T>G that creates a new intronic 3\' acceptor splice site, had quite a typical clinical presentation of NF1: formations on her tongue in the region of her left metacarpal bones and on her left foot, plexiform neurofibroma in her pelvis, several café-au-lait spots, and axillary freckling. She was also diagnosed with cognitive impairment. In the report, we are presenting two novel variants which were successfully classified based on NGS and mRNA analysis. Based on results of mRNA analysis, both variants were classified as likely pathogenic according to ACMG guidelines applying evidence categories PS3, PM2, PP3, and PP1 supporting. By characterizing those two novel NF1 splicing variants, we have confirmed the neurofibromatosis type I phenotype in the two probands.