Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.
Mol Genet Metab
; 141(3): 108118, 2024 Mar.
Article
in En
| MEDLINE
| ID: mdl-38244286
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pelger-Huet Anomaly
/
Liver Failure, Acute
/
Neuroblastoma
Type of study:
Guideline
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Mol Genet Metab
Journal subject:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
METABOLISMO
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: