NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype–phenotype correlations. Issue 6 (18th March 2019) - Carli, Diana
Abstract: 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. Abstract : NBAS mutations‐associated facial profile. NBAS variants and genotype–phenotype correlation. Novel NBAS synonymous change‐affecting exon 51 splicing.