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