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.

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

Carli, Diana;Giorgio, Elisa;Riberi, Evelise;LICCIARDI, FRANCESCO;GAZZIN, ANDREA;Baldassarre, Giuseppina;Molinatto, Cristina;Montin, Davide;Ferrero, Giovanni Battista;Brusco, Alfredo;
2019

Abstract

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.
HUMAN MUTATION
40
721
728
https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23734
NBAS; acute liver failure; face2gene; facial recognition technology; genotype-phenotype correlation; splicing variant
Carli, Diana; Giorgio, Elisa; Pantaleoni, Francesca; Bruselles, Alessandro; Barresi, Sabina; Riberi, Evelise; Licciardi, Francesco; Gazzin, Andrea; Baldassarre, Giuseppina; Pizzi, Simone; Niceta, Marcello; Radio, Francesca Clementina; Molinatto, Cristina; Montin, Davide; Calvo, Pier Luigi; Ciolfi, Andrea; Fleischer, Nicole; Ferrero, Giovanni Battista; Brusco, Alfredo; Tartaglia, Marco
File in questo prodotto:
File Dimensione Formato  
Carli_et_al-2019-Human_Mutation (1).pdf

non disponibili

Tipo di file: PDF EDITORIALE
Dimensione 711.4 kB
Formato Adobe PDF
711.4 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Carli_et_al-2019-Human_Mutation.pdf

non disponibili

Descrizione: Cover
Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 2 MB
Formato Adobe PDF
2 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
NBAS_R1_pre print.docx

non disponibili

Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 1.09 MB
Formato Adobe PDF
1.09 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
NBAS_R1_pre print.pdf

accesso aperto

Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 592.8 kB
Formato Adobe PDF
592.8 kB Adobe PDF Visualizza/Apri
138_A_NBAS_HumanMut2019.pdf

non disponibili

Tipo di file: PDF EDITORIALE
Dimensione 711.4 kB
Formato Adobe PDF
711.4 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1694271
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 13
  • ???jsp.display-item.citation.isi??? 12
social impact