PuSH - Publication Server of Helmholtz Zentrum München

Hammann, N.* ; Lenz, D.* ; Baric, I.* ; Crushell, E.* ; Vici, C.D.* ; Distelmaier, F.* ; Feillet, F.* ; Freisinger, P.* ; Hempel, M.* ; Khoreva, A.L.* ; Laass, M.W.* ; Lacassie, Y.* ; Lainka, E.* ; Larson-Nath, C.* ; Li, Z.* ; Lipiński, P.* ; Lurz, E.* ; Megarbane, A.* ; Nobre, S.* ; Olivieri, G.* ; Peters, B.* ; Prontera, P.* ; Schlieben, L.D. ; Seroogy, C.M.* ; Sobacchi, C.* ; Suzuki, S.C.* ; Tran, C.L.* ; Vockley, J.* ; Wang, J.S.* ; Wagner, M. ; Prokisch, H. ; Garbade, S.F.* ; Kolker, S.* ; Hoffmann, G.F.* ; Staufner, C.*

Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.

Mol. Genet. Metab. 141:108118 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Genotype-phenotype Correlation ; Ilfs2 ; Nbas ; Recurrent Acute Liver Failure ; Soph; Acute Liver-failure; Amplified Sequence Gene; Hepatic-failure; Soph Syndrome; Mutations; Deficiency; Children; Features; Onset; Bone
ISSN (print) / ISBN 1096-7192
e-ISSN 1096-7192
Journal Molecular Genetics and Metabolism
Quellenangaben Volume: 141, Issue: 3, Pages: , Article Number: 108118 Supplement: ,
Publisher Elsevier
Publishing Place 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants Deutsche Leberstiftung
Dietmar Hopp Foundation, St. Leon -Rot, Germany