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

Autor: Hammann N; Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany., Lenz D; Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany., Baric I; Department of Paediatrics, University Hospital Center Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia., Crushell E; National Centre for Inherited Metabolic Disorders, Childrens Health Ireland, Temple Street, Dublin 1, Ireland., Vici CD; Division of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy., Distelmaier F; Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany., Feillet F; Department of Paediatrics, Hôpital d'Enfants Brabois, CHU Nancy, Vandoeuvre les Nancy, France., Freisinger P; Children's Hospital Reutlingen, Germany., Hempel M; Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany., Khoreva AL; Dmitry Rogachev National Research Center for Pediatric Hematology, Oncology, Immunology Moscow, Russia., Laass MW; Department of Pediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Lacassie Y; Department of Pediatrics, Division of Genetics, LSU Health Sciences Center and Children's Hospital, New Orleans, Louisiana, USA., Lainka E; Pediatrics II, Department for Pediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Larson-Nath C; Pediatric Gastroenterology, University of Minnesota Medical School, Minneapolis, MN, USA., Li Z; Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China., Lipiński P; Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland., Lurz E; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany., Mégarbané A; Department of Human Genetics Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon; Institut Jérôme Lejeune, Paris, France., Nobre S; Pediatric Hepatology and Liver Transplantation Unit, Pediatric Department, Coimbra Hospital and Universitary Centre, Coimbra, Portugal., Olivieri G; Division of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy., Peters B; Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany., Prontera P; Medical Genetics Unit, Maternal-Infantile Department, Hospital and University of Perugia, Perugia, Italy., Schlieben LD; School of Medicine, Institute of Human Genetics, Technische Universität München, Munich, Germany; Department Computational Health, Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany., Seroogy CM; Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin-Madison, USA., Sobacchi C; Humanitas Research Hospital IRCCS, Rozzano, Italy; Institute for Genetic and Biomedical Research-National Research Council, Milan Unit, Milan, Italy., Suzuki S; Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan., Tran C; Division of Genetic Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland., Vockley J; University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA., Wang JS; Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China., Wagner M; School of Medicine, Institute of Human Genetics, Technische Universität München, Munich, Germany; Department Computational Health, Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany., Prokisch H; School of Medicine, Institute of Human Genetics, Technische Universität München, Munich, Germany; Department Computational Health, Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany., Garbade SF; Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany., Kölker S; Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany., Hoffmann GF; Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany., Staufner C; Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany. Electronic address: Christian.Staufner@med.uni-heidelberg.de.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2024 Mar; Vol. 141 (3), pp. 108118. Date of Electronic Publication: 2024 Jan 11.
DOI: 10.1016/j.ymgme.2023.108118
Abstrakt: 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.
Competing Interests: Declaration of competing interest None.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE