Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.
Details
State: Public
Version: Final published version
License: CC BY-NC 4.0
Serval ID
serval:BIB_C34190170CCC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.
Journal
Molecular genetics and metabolism
ISSN
1096-7206 (Electronic)
ISSN-L
1096-7192
Publication state
Published
Issued date
03/2024
Peer-reviewed
Oui
Volume
141
Number
3
Pages
108118
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.
Keywords
Humans, Phenotype, Pelger-Huet Anomaly/complications, Pelger-Huet Anomaly/genetics, Pelger-Huet Anomaly/pathology, Liver Failure, Acute/genetics, Mutation, Missense, Neuroblastoma/complications, Genotype-phenotype correlation, ILFS2, NBAS, Recurrent acute liver failure, SOPH
Pubmed
Web of science
Open Access
Yes
Create date
26/01/2024 14:11
Last modification date
06/04/2024 7:23