Nicole Hammann, Universität Heidelberg
Dominic Lenz, Universität Heidelberg
Ivo Baric, KBC Zagreb
Ellen Crushell, National Centre for Inherited Metabolic Disorders
Carlo Dionisi Vici, IRCCS Ospedale Pediatrico Bambino Gesù
Felix Distelmaier, Universitätsklinikum Düsseldorf
Francois Feillet, Hôpital Brabois Adultes
Peter Freisinger, Children's Hospital Reutlingen
Maja Hempel, Universitätsklinikum Heidelberg
Anna L. Khoreva, Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
Martin W. Laass, Universitätsklinikum Carl Gustav Carus Dresden
Yves Lacassie, LSU Health Sciences Center - New OrleansFollow
Elke Lainka, Universitätsklinikum Essen
Catherine Larson-Nath, University of Minnesota Medical School
Zhongdie Li, Children’s Hospital of Fudan University
Patryk Lipiński, Instytut "Pomnik - Centrum Zdrowia Dziecka"
Eberhard Lurz, Klinikum der Universität München
André Mégarbané, Gilbert and Rose-Marie Chagoury School of Medicine
Susana Nobre, Centro Hospitalar e Universitário de Coimbra
Giorgia Olivieri, IRCCS Ospedale Pediatrico Bambino Gesù
Bianca Peters, Universität Heidelberg
Paolo Prontera, Università degli Studi di Perugia
Lea D. Schlieben, TUM Fakultät für Medizin
Christine M. Seroogy, University of Wisconsin-Madison
Cristina Sobacchi, Humanitas Research Hospital
Shigeru Suzuki, Asahikawa Medical University
Christel Tran, Centre Hospitalier Universitaire Vaudois
Jerry Vockley, UPMC Children’s Hospital of Pittsburgh

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Molecular Genetics and Metabolism


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.

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Creative Commons Attribution-NonCommercial 4.0 International License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License