神经纤维瘤病1型（NF1）是一种常染色体显性、单倍体不足和多系统障碍疾病，表现为咖啡牛奶斑块、虹膜里斯结节，甚至是外周神经系统或纤维肉瘤皮肤肿瘤。本研究招募了一位患有NF1疾病并在第一孕期发生自然流产的中国年轻女性。进行了全外显子测序（WES）、Sanger测序、短串联重复（STR）和共分离分析。结果发现，原发者中有一种新的、杂合的、去泛素化致病变异体（c.4963delA:p.Thr1656Glnfs*42），属自发的，是NF1基因的一个致病变异体。这种NF1基因的致病变异体产生了一个缩短的蛋白质，在C-端失去了超过三分之一的NF1蛋白质，包括CRAL-TRIO脂质结合域和核定位信号（NLS）的一半，因此导致病理性（ACMG标准：PVS1+PM2+PM2）。物种中NF1的保守性分析显示不同物种的高度保守性。不同人类组织中NF1 mRNA水平的分析显示组织特异性较低，可能影响多器官出现的其它症状或表型。此外，产前NF1基因诊断显示两个等位基因均为野生型。因此，这种NF1新变异体可能是这个家系NF1发病的原因，这将有助于该疾病的诊断、遗传咨询和临床管理。© 2023. The Author(s).

Neurofibromatosis type 1 (NF1) presents an autosomal dominant, haploinsufficient, and multisystemic disorder with patches of skin café-au-lait spots, lisch nodules in the iris, even tumors in the peripheral nervous system or fibromatous skin. In this study, a Chinese young woman who suffered from NF1 disease with first-trimester spontaneous abortion was recruited. Analysis for whole exome sequencing (WES), Sanger sequencing, short tandem repeat (STR), and co-segregation was carried out. As results, a novel, heterozygous, de novo pathogenic variant (c.4963delA:p.Thr1656Glnfs*42) of the NF1 gene in the proband was identified. This pathogenic variant of the NF1 gene produced a truncated protein that lost more than one-third of the NF1 protein at the C-terminus including half of the CRAL-TRIO lipid-binding domain and nuclear localization signal (NLS), thus leading to pathogenicity (ACMG criteria: PVS1 + PM2 + PM2). Analysis for NF1 conservation in species revealed high conservation in different species. Analysis of NF1 mRNA levels in different human tissues showed low tissue specificity, which may affect multiple organs presenting other symptoms or phenotypes. Moreover, prenatal NF1 gene diagnosis showed both alleles as wild types. Thus, this NF1 novel variant probably underlays the NF1 pathogenesis in this pedigree, which would help for the diagnosis, genetic counseling, and clinical management of this disorder.© 2023. The Author(s).