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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.

Author information

1
Department of Public Health and Pediatrics, University of Torino, Torino, Italy.
2
Department of Medical Sciences, University of Torino, Torino, Italy.
3
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy.
4
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
5
Pediatric Gastroenterology Unit, Città della Salute e della Scienza University Hospital, Torino, Italy.
6
FDNA Inc, Boston, Massachusetts.
7
Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy.

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.

KEYWORDS:

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

PMID:
30825388
DOI:
10.1002/humu.23734

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