Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:141 |
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| Enthalten in: |
Molecular genetics and metabolism - 141(2024), 3 vom: 09. März, Seite 108118 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hammann, Nicole [VerfasserIn] |
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| Links: |
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| Themen: |
Genotype-phenotype correlation |
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| Anmerkungen: |
Date Completed 11.03.2024 Date Revised 11.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ymgme.2023.108118 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Genotype-phenotype correlation | |
| 650 | 4 | |a ILFS2 | |
| 650 | 4 | |a NBAS | |
| 650 | 4 | |a Recurrent acute liver failure | |
| 650 | 4 | |a SOPH | |
| 700 | 1 | |a Lenz, Dominic |e verfasserin |4 aut | |
| 700 | 1 | |a Baric, Ivo |e verfasserin |4 aut | |
| 700 | 1 | |a Crushell, Ellen |e verfasserin |4 aut | |
| 700 | 1 | |a Vici, Carlo Dionisi |e verfasserin |4 aut | |
| 700 | 1 | |a Distelmaier, Felix |e verfasserin |4 aut | |
| 700 | 1 | |a Feillet, Francois |e verfasserin |4 aut | |
| 700 | 1 | |a Freisinger, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Hempel, Maja |e verfasserin |4 aut | |
| 700 | 1 | |a Khoreva, Anna L |e verfasserin |4 aut | |
| 700 | 1 | |a Laass, Martin W |e verfasserin |4 aut | |
| 700 | 1 | |a Lacassie, Yves |e verfasserin |4 aut | |
| 700 | 1 | |a Lainka, Elke |e verfasserin |4 aut | |
| 700 | 1 | |a Larson-Nath, Catherine |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhongdie |e verfasserin |4 aut | |
| 700 | 1 | |a Lipiński, Patryk |e verfasserin |4 aut | |
| 700 | 1 | |a Lurz, Eberhard |e verfasserin |4 aut | |
| 700 | 1 | |a Mégarbané, André |e verfasserin |4 aut | |
| 700 | 1 | |a Nobre, Susana |e verfasserin |4 aut | |
| 700 | 1 | |a Olivieri, Giorgia |e verfasserin |4 aut | |
| 700 | 1 | |a Peters, Bianca |e verfasserin |4 aut | |
| 700 | 1 | |a Prontera, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Schlieben, Lea D |e verfasserin |4 aut | |
| 700 | 1 | |a Seroogy, Christine M |e verfasserin |4 aut | |
| 700 | 1 | |a Sobacchi, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Suzuki, Shigeru |e verfasserin |4 aut | |
| 700 | 1 | |a Tran, Christel |e verfasserin |4 aut | |
| 700 | 1 | |a Vockley, Jerry |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jian-She |e verfasserin |4 aut | |
| 700 | 1 | |a Wagner, Matias |e verfasserin |4 aut | |
| 700 | 1 | |a Prokisch, Holger |e verfasserin |4 aut | |
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| 700 | 1 | |a Staufner, Christian |e verfasserin |4 aut | |
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