A novel compound heterozygous NBAS variant with HLH and multisystem involvement: expanding the clinical spectrum and literature review.

Biallelic variants in the neuroblastoma amplified sequence (NBAS) gene have been associated with short stature, optic atrophy, and Pelger-Huët anomaly (SOPH) syndrome, infantile liver failure syndrome type 2 (ILFS-2), and an increasingly broad spectrum of clinical phenotypes. However, cases presenting with hemophagocytic lymphohistiocytosis (HLH) accompanied by immune dysfunction and multisystem involvement have not been reported. We identified novel compound heterozygous variants in the NBAS gene, c.5139-5T>G and c.5983C>T, in a Chinese girl who successively developed recurrent infections, short stature, ILFS-2, progressive cytopenias from leukopenia to bicytopenia and eventually pancytopenia, and HLH. Polymerase chain reaction confirmed that c.5139-5T>G variant caused aberrant splicing. The c.5983C>T variant is novel and was classified as likely pathogenic according to American College of Medical Genetics and Genomics guidelines. Western blotting of the patient's PBMCs detected only a truncated NBAS protein, consistent with the product predicted from the c.5983C>T variant. Functional studies in HEK293T cells overexpressing the truncated NBAS protein further indicated impaired NBAS function, as assessed by real-time quantitative reverse transcription polymerase chain reaction and immunofluorescence analysis. We systematically reviewed 322 previously reported patients and analyzed genotype-phenotype correlations in 316 cases to further define the clinical spectrum of NBAS-related disease. We identified a novel pathogenic NBAS variant, further expanded the phenotypic spectrum of NBAS-related disease, and provided additional insight into genotype-phenotype correlations. Pancytopenia and HLH may reflect severe immune dysregulation and poor prognosis, highlighting the importance of early recognition and timely intervention.