Clinical report
A 34-year-old Japanese patient exhibiting NBAS deficiency with a novel mutation and extended phenotypic variation

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Abstract

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.

Introduction

The biallelic neuroblastoma amplified sequence (NBAS) gene has recently been identified as the causative gene for two apparently distinct syndromes: short stature, optic nerve atrophy, and Pelger–Huët anomaly (SOPH, MIM614800) syndrome and infantile liver failure syndrome 2 (ILFS2, MIM616483). SOPH was originally reported in the Yakuts population, with a specific founder variant, p.Arg1914His (Maksimova et al., 2010). On the other hand, ILFS2 is characterized by recurrent acute liver failure (RALF) during intercurrent febrile illness (Haack et al., 2015). However, increasing evidence indicates that the NBAS pathogenic variants cause a reduction in its protein expression and multi-systemic diseases, including skeletal dysplasia and immunological and neurological abnormalities; this has led to the naming of this condition as NBAS deficiency (Staufner et al., 2020).

The NBAS protein has two biological functions; one is in Golgi-to-ER retrograde vesicular trafficking and the other is associated with controlling nonsense-mediated mRNA decay (NMD) (Hug et al., 2016). The ubiquitous expression of NBAS protein may explain why NBAS deficiency leads to diverse phenotypes in patients. The NBAS gene consists of 52 exons, and encodes 2371 deduced amino acid sequences. The predicted secondary protein structure is roughly divided into three regions: β-propeller, Sec39, and C-terminal (Staufner et al., 2020). Staufner et al. (2020) examined the genotype–phenotype correlation in 110 patients, and showed that it was mainly determined by the localization of missense variants and in-frame deletions rather than the loss-of-function variants in another allele, i.e., β-propeller (combined phenotype), Sec39 (ILFS2), and C-terminal (multi-systemic features other than ILFS2).

However, because NBAS deficiency is a very rare disease with high genetic heterogeneity, the knowledge on this condition and its characterization remain incomplete. Clinically, information on the natural course has been obviously scant because more than 90% of the patients reported are under 20 years of age, and more than half are younger than 10 (Staufner et al., 2020). In addition, as the variants are found throughout the gene (Staufner et al., 2020), the accumulation of new patients is needed to robustly establish the genotype–phenotype relationships.

Herein, we report a 34-year-old patient with novel clinical features in addition to a whole range of phenotypes for NBAS deficiency due to compound heterozygous variants, of which one is novel; both are located at the C-terminal.

Section snippets

Methods

The patient and his relatives provided written informed consent for clinical or genetic testing and research use. The study was approved by the Institutional Review Board of Asahikawa Medical University.

Clinical description

The male patient, aged 34 years, whose phenotypic features at different ages shown in Fig. 1, was born as a second child, after 40 weeks of gestation, to Japanese non-consanguineous parents. His parents and brother had no particular medical history. He was small for his gestational age, with a birth weight of 2364 g (−2.99 SD), length of 46 cm (−2.14 SD), and occipital frontal circumference of 32 cm (−1.27 SD). At birth, his fontanel was markedly open (Fig. 1A). He had hard skin (similar to

Discussion

NBAS deficiency is currently recognized as a rare complex genetic disorder with abnormalities in the liver, bone, integument, and immune and nervous systems (Staufner et al., 2020). However, the long-term prognosis is largely unknown because only 4 adult patients with this disorder have been reported (Lacassie et al., 2020; Staufner et al., 2016; Maksimova et al., 2010). In addition, only 12% (13/110) of patients with NBAS deficiency have a wide range of phenotypic features (Staufner et al. 2016

Funding

The authors received no specific funding for this work.

CRediT authorship contribution statement

Shigeru Suzuki: Conceptualization, Investigation, Writing - original draft, Project administration. Takahide Kokumai: Investigation. Akiko Furuya: Investigation. Tsunehisa Nagamori: Investigation. Kumihiro Matsuo: Investigation. Osamu Ueda: Investigation. Tokuo Mukai: Investigation. Yoshiya Ito: Investigation. Koichi Yano: Investigation. Kenji Fujieda: Resources, Supervision. Akimasa Okuno: Investigation, Supervision. Yusuke Tanahashi: Investigation, Resources, Writing - review & editing.

Declaration of competing interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank the present family for their cooperation with this publication. We appreciate the numerous physicians, nurses, and other specialists who provided outstanding care for this patient for many years; Ms. Nami Iguchi and Ms. Risa Taniguchi for technical support in molecular analysis; and Drs. Koji Sawada from the Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Reiko Kinoshita from the Department of Ophthalmology, and Shinsuke Yoshihara from the Department of

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