NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype-phenotype correlations

Diana Carli, Elisa Giorgio, Francesca Pantaleoni, Alessandro Bruselles, Sabina Barresi, Evelise Riberi, Francesco Licciardi, Andrea Gazzin, Giuseppina Baldassarre, Simone Pizzi, Marcello Niceta, Francesca C Radio, Cristina Molinatto, Davide Montin, Pier L Calvo, Andrea Ciolfi, Nicole Fleischer, Giovanni B Ferrero, Alfredo Brusco, Marco Tartaglia

Research output: Contribution to journalArticlepeer-review


The pathogenic variants in the neuroblastoma-amplified sequence (NBAS) are associated with a clinical spectrum involving the hepatic, skeletal, ocular, and immune systems. Here, we report on two unrelated subjects with a complex phenotype solved by whole-exome sequencing, who shared a synonymous change in NBAS that was documented to affect the transcript processing and co-occurring with a truncating change. Starting from these two cases, we systematically assessed the clinical information available for all subjects with biallelic NBAS pathogenic variants (73 cases in total). We revealed a recognizable facial profile (hypotelorism, thin lips, pointed chin, and "progeroid" appearance) determined by using DeepGestalt facial recognition technology, and we provide evidence for the occurrence of genotype-phenotype correlations. Notably, severe hepatic involvement was associated with variants affecting the NBAS-Nter and Sec39 domains, whereas milder liver involvement and immunodeficiency were generally associated with variants located at the N-terminus and C-terminus of the protein. Remarkably, no patient was reported to carry two nonsense variants, suggesting lethality of complete NBAS loss-of-function.

Original languageEnglish
JournalHuman Mutation
Publication statusE-pub ahead of print - Mar 2 2019


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