Document Type
Article
Publication Date
1-11-2024
Publication Title
Molecular Genetics and Metabolism
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.
PubMed ID
38244286
Volume
141
Issue
3
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
Recommended Citation
Hammann, Nicole; Lenz, Dominic; Baric, Ivo; Crushell, Ellen; Vici, Carlo Dionisi; Distelmaier, Felix; Feillet, Francois; Freisinger, Peter; Hempel, Maja; Khoreva, Anna L.; Laass, Martin W.; Lacassie, Yves; Lainka, Elke; Larson-Nath, Catherine; Li, Zhongdie; Lipiński, Patryk; Lurz, Eberhard; Mégarbané, André; Nobre, Susana; Olivieri, Giorgia; Peters, Bianca; Prontera, Paolo; Schlieben, Lea D.; Seroogy, Christine M.; Sobacchi, Cristina; Suzuki, Shigeru; Tran, Christel; and Vockley, Jerry, "Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease" (2024). School of Medicine Faculty Publications. 2099.
https://digitalscholar.lsuhsc.edu/som_facpubs/2099
Included in
Hepatology Commons, Medical Genetics Commons, Pediatrics Commons