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

Pathogenic variants in 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 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 Sec. 39 domains, while 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. This article is protected by copyright. All rights reserved.