Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease
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 syn...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 2024
|
| In: |
Molecular genetics and metabolism
Year: 2024, Volume: 141, Issue: 3, Pages: 1-10 |
| ISSN: | 1096-7206 |
| DOI: | 10.1016/j.ymgme.2023.108118 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.ymgme.2023.108118 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1096719223007485 
|
| Author Notes: | Nicole Hammann, Dominic Lenz, Ivo Baric, Ellen Crushell, Carlo Dionisi Vici, Felix Distelmaier, Francois Feillet, Peter Freisinger, Maja Hempel, Anna L. Khoreva, Martin W. Laass, Yves Lacassie, Elke Lainka, Catherine Larson-Nath, Zhongdie Li, Patryk Lipiński, Eberhard Lurz, André Mégarbané, Susana Nobre, Giorgia Olivieri, Bianca Peters, Paolo Prontera, Lea D. Schlieben, Christine M. Seroogy, Cristina Sobacchi, Shigeru Suzuki, Christel Tran, Jerry Vockley, Jian-She Wang, Matias Wagner, Holger Prokisch, Sven F. Garbade, Stefan Kölker, Georg F. Hoffmann, Christian Staufner |
| Summary: | 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. |
|---|---|
| Item Description: | Online verfügbar: 11. Januar 2024, Artikelversion: 19. Januar 2024 Gesehen am 16.09.2024 |
| Physical Description: | Online Resource |
| ISSN: | 1096-7206 |
| DOI: | 10.1016/j.ymgme.2023.108118 |