Biallelic neuroblastoma amplified sequence (NBAS) gene mutations have recently been identified to cause a reduction in its protein expression and a broad phenotypic spectrum, from isolated short stature, optic nerve atrophy, and Pelger–Huët anomaly (SOPH) syndrome or infantile liver failure syndrome 2 to a combined, multi-systemic disease including skeletal dysplasia and immunological and neurological abnormalities. Herein, we report a 34-year-old patient with a range of phenotypes for NBAS deficiency due to compound heterozygous variants; one is a SOPH-specific variant, p.Arg1914His, and the other is a novel splice site variant, c.6433-2A>G. The patient experienced recurrent acute liver failure until early childhood. Hypogammaglobulinemia, a decrease in natural killer cells, and optic nerve atrophy were evident from infancy to childhood. In adulthood, the patient exhibited novel phenotypic features such as hepatic cirrhosis complicated by portal hypertension and autoimmune hemolytic anemia. The patient also suffered from childhood-onset insulin-requiring diabetes with progressive beta cell dysfunction. The patient had severe short stature and exhibited dysmorphic features compatible with SOPH, intellectual disability, and epilepsy. NBAS protein expression in the patient's fibroblasts was severely low. RNA expression analysis for the c.6433-2A>G variant showed that this variant activated two cryptic splice sites in intron 49 and exon 50, for which the predicted consequences at the protein level were an in-frame deletion/insertion, p.(Ile2199_Asn2202delins16), and a premature termination codon, p.(Ile2199Tyrfs*17), respectively. These findings indicate that NBAS deficiency is a multi-systemic progressive disease. The results of this study extend the spectrum of clinical and genetic findings related to NBAS deficiency.

双等位神经母细胞瘤扩增序列（NBAS）最近发现基因突变会导致其蛋白质表达降低和广泛的表型谱，从孤立的矮小身材，视神经萎缩和佩尔格-休伊特综合征（SOPH）综合征或婴儿肝衰竭综合征2到综合性多发-全身疾病，包括骨骼发育不良以及免疫和神经异常。本文中，我们报道了一名34岁患者，由于复合杂合变异体而存在一系列NBAS缺乏症的表型。一个是SOPH特异性变体p.Arg1914His，另一个是新的剪接位点变体c.6433-2A> G。患者经历了反复发作的急性肝衰竭，直到儿童早期。从婴儿期到儿童期，明显存在低球蛋白血症，自然杀伤细胞减少和视神经萎缩。成年后 患者表现出新的表型特征，例如肝硬化并发门脉高压和自身免疫性溶血性贫血。该患者还患有儿童期糖尿病，并伴有进行性β细胞功能障碍。该患者身材矮小，表现出与SOPH，智力障碍和癫痫病相适应的畸形特征。病人成纤维细胞中的NBAS蛋白表达严重降低。对c.6433-2A> G变体的RNA表达分析表明，该变体激活了内含子49和外显子50中的两个隐蔽剪接位点，其在蛋白质水平的预期后果是框内缺失/插入p。（ Ile2199_Asn2202delins16）和过早终止密码子p。（Ile2199Tyrfs * 17）。这些发现表明，NBAS缺乏症是一种多系统的进行性疾病。这项研究的结果扩展了与NBAS缺乏症相关的临床和遗传发现的范围。