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Hum Mutat. 2019 Mar 2. doi: 10.1002/humu.23734. [Epub ahead of print]

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

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Department of Public Health and Pediatrics, University of Torino, Torino, Italy.
Department of Medical Sciences, University of Torino, Torino, Italy.
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy.
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Pediatric Gastroenterology Unit, Città della Salute e della Scienza University Hospital, Torino, Italy.
FDNA Inc, Boston, Massachusetts.
Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy.


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.


NBAS; acute liver failure; face2gene; facial recognition technology; genotype-phenotype correlation; splicing variant


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