Complex Multisystem Phenotype With Immunodeficiency Associated With NBAS Mutations: Reports of Three Patients and Review of the Literature

Abstract

Objectives: Mutations in the neuroblastoma-amplified sequence (NBAS) gene were originally described in patients with skeletal dysplasia or isolated liver disease of variable severity. Subsequent publications reported a more complex phenotype. Among multisystemic clinical symptoms, we were particularly interested in the immunological consequences of the NBAS deficiency. Methods: Clinical and laboratory data of 3 patients ages 13, 6, and 5 in whom bi-allelic NBAS mutations had been detected via next-generation sequencing were characterized. Literature review of 23 publications describing 74 patients was performed. Results: We report three Russian patients with compound heterozygous mutations of the NBAS gene who had combined immunodeficiency characterized by hypogammaglobulinemia, low T-cells, and near-absent B-cells, along with liver disease, skeletal dysplasia, optic-nerve atrophy, and dysmorphic features. Analysis of the data of 74 previously reported patients who carried various NBAS mutations demonstrated that although the most severe form of liver disease seems to require disruption of the N-terminal or middle part of NBAS, mutations of variable localizations in the gene have been associated with some form of liver disease, as well as immunological disorders. Conclusions: NBAS deficiency has a broad phenotype, and referral to an immunologist should be made in order to screen for immunodeficiency.

WES Reveals Novel Heterozygous NBAS Gene Mutations Associated with Fanconi Syndrome in a Patient with SOPH Syndrome: Case Report

“…Other authors showed how the aetiology of biallelic mutations in the NBAS gene resulted in recurrent episodes of acute liver failure, as shown in our study [4,6,27,28,30,31]. Nonetheless, these two mutations were not identified in any of these studies, thus indicating their significance in causing abnormal liver function and Fanconi syndrome in SOPH patients.…”

Origins of SOPH syndrome: A study of 93 Yakut patients with review of C‐terminal phenotype

“…We strived to perform a comparative analysis between the phenotypes of SOPH patients and carriers of the p. Arg1914His variant in the compound heterozygous state. In total, we have found the descriptions of 17 cases with compound heterozygosity in the available literature 6,10‐16 . Genetic variants other than p. Arg1914His in the NBAS gene included 1 missense, 7 nonsense, 4 frameshift, 3 splice‐site variants, and 2 long in‐frame deletions.…”

“…We strived to perform a comparative analysis between the phenotypes of SOPH patients and carriers of the p. Arg1914His variant in the compound heterozygous state. In total, we have found the descriptions of 17 cases with compound heterozygosity in the available literature 6,[10][11][12][13][14][15][16] . We did not find any specific traits regarding the cardiovascular, endocrinological, and the hematopoietic systems.…”

Chromosomal aberrations as the cause of a complex phenotype in children with primary immunodeficiencies

“…В случаях сиблингов из 2 различных семейпациенты №3 и 4 и пациенты №5 и 6 -изначально при помощи метода NGS были обнаружены гетерозиготные мутации в соответствующих генах: в семье пациентов №3 и 4 -в гене DCLRE1C: NM_001033855: c.1478_1479delTT (p.Phe493*) и в семье пациентов №5 и 6 -в гене NBAS: NM_015909: c.5741G>A (p.Arg1914His) [20]. Клиническая и лабораторная картина сиблингов в первой семье соответствовала комбинированному иммунодефициту, во второй семье -иммунодефициту с проявлениями несовершенного остеогенеза.…”