Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients

Christian Staufner¹, Bianca Peters¹, Matias Wagner^{2

3

4}, Seham Alameer⁵, Ivo Barić⁶, Pierre Broué⁷, Derya Bulut⁸, Joseph A Church⁹, Ellen Crushell¹⁰, Buket Dalgıç¹¹, Anibh M Das¹², Anke Dick¹³, Nicola Dikow¹⁴, Carlo Dionisi-Vici¹⁵, Felix Distelmaier¹⁶, Neslihan Ekşi Bozbulut¹¹, François Feillet¹⁷, Emmanuel Gonzales¹⁸, Nedim Hadzic¹⁹, Fabian Hauck²⁰, Robert Hegarty¹⁹, Maja Hempel²¹, Theresia Herget²¹, Christoph Klein²⁰, Vassiliki Konstantopoulou²², Robert Kopajtich^{2

3}, Alice Kuster²³, Martin W Laass²⁴, Elke Lainka²⁵, Catherine Larson-Nath²⁶, Alexander Leibner¹, Eberhard Lurz²⁰, Johannes A Mayr²⁷, Patrick McKiernan²⁸, Karine Mention²⁹, Ute Moog¹⁴, Neslihan Onenli Mungan⁸, Korbinian M Riedhammer^{2

3

30}, René Santer³¹, Irene Valenzuela Palafoll³², Jerry Vockley²⁸, Dominik S Westphal^{2

3}, Arnaud Wiedemann¹⁷, Saskia B Wortmann^{2

3

27}, Gaurav D Diwan^{33

34}, Robert B Russell^{33

34}, Holger Prokisch^{2

3}, Sven F Garbade¹, Stefan Kölker¹, Georg F Hoffmann¹, Dominic Lenz³⁵

Affiliations

¹ Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
² Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Munich, Germany.
³ Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany.
⁴ Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
⁵ Department of Pediatrics, King Khaled National Guard Hospital, Jeddah, Saudi Arabia.
⁶ Department of Pediatrics, University Hospital Center Zagreb and University of Zagreb, School of Medicine, Zagreb, Croatia.
⁷ Pediatric Gastroenterology, Hepatology and Nutrition unit, Reference Center for Inherited Metabolic Diseases, Children's Hospital, Toulouse University Hospital, Toulouse, France.
⁸ Cukurova University Medical Faculty, Department of Pediatric Metabolism, Adana, Turkey.
⁹ Department of Pediatrics, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, USA.
¹⁰ National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
¹¹ Gazi University Faculty of Medicine, Department of Pediatric Gastroenterology, Ankara, Turkey.
¹² Clinic for Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
¹³ Department of Pediatrics, University Hospital Würzburg, Wuerzburg, Germany.
¹⁴ Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
¹⁵ Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy.
¹⁶ Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
¹⁷ Department of Pediatrics, INSERM 1256, Hôpital d'Enfants Brabois, CHU Nancy, Vandoeuvre les Nancy, France.
¹⁸ Pediatric Hepatology and Pediatric Liver Transplantation Unit, Bicêtre Hospital, AP-HP Paris-Sud University, Le Kremlin-Bicêtre, France.
¹⁹ Pediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, UK.
²⁰ Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
²¹ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²² Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
²³ Inborn Errors of Metabolism, Pediatric Intensive Care Unit, University Hospital of Nantes, Nantes, France.
²⁴ Children's Hospital, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
²⁵ Children's Hospital, Department of Pediatric Gastroenterology, Hepatology, and Transplant Medicine, University Duisburg-Essen, Essen, Germany.
²⁶ Pediatric Gastroenterology, University of Minnesota Medical School, Minneapolis, MN, USA.
²⁷ Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.
²⁸ University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
²⁹ Reference Center for Inherited Metabolic Diseases, Jeanne de Flandres Hospital, Lille, France.
³⁰ Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
³¹ Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³² Department of Clinical Genetics and Molecular Genetics, Hospital Vall d'Hebron, Barcelona, Spain.
³³ CellNetworks, Bioquant, Heidelberg University, Heidelberg, Germany.
³⁴ Biochemie Zentrum Heidelberg (BZH), Heidelberg University, Heidelberg, Germany.
³⁵ Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. Dominic.Lenz@med.uni-heidelberg.de.

PMID: 31761904
DOI: 10.1038/s41436-019-0698-4

Free article

Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients

Christian Staufner et al. Genet Med. 2020 Mar.

Free article

. 2020 Mar;22(3):610-621.

doi: 10.1038/s41436-019-0698-4. Epub 2019 Nov 25.

Authors

Affiliations

¹ Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
² Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Munich, Germany.
³ Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany.
⁴ Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
⁵ Department of Pediatrics, King Khaled National Guard Hospital, Jeddah, Saudi Arabia.
⁶ Department of Pediatrics, University Hospital Center Zagreb and University of Zagreb, School of Medicine, Zagreb, Croatia.
⁷ Pediatric Gastroenterology, Hepatology and Nutrition unit, Reference Center for Inherited Metabolic Diseases, Children's Hospital, Toulouse University Hospital, Toulouse, France.
⁸ Cukurova University Medical Faculty, Department of Pediatric Metabolism, Adana, Turkey.
⁹ Department of Pediatrics, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, USA.
¹⁰ National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
¹¹ Gazi University Faculty of Medicine, Department of Pediatric Gastroenterology, Ankara, Turkey.
¹² Clinic for Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
¹³ Department of Pediatrics, University Hospital Würzburg, Wuerzburg, Germany.
¹⁴ Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
¹⁵ Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy.
¹⁶ Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
¹⁷ Department of Pediatrics, INSERM 1256, Hôpital d'Enfants Brabois, CHU Nancy, Vandoeuvre les Nancy, France.
¹⁸ Pediatric Hepatology and Pediatric Liver Transplantation Unit, Bicêtre Hospital, AP-HP Paris-Sud University, Le Kremlin-Bicêtre, France.
¹⁹ Pediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, UK.
²⁰ Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
²¹ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²² Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
²³ Inborn Errors of Metabolism, Pediatric Intensive Care Unit, University Hospital of Nantes, Nantes, France.
²⁴ Children's Hospital, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
²⁵ Children's Hospital, Department of Pediatric Gastroenterology, Hepatology, and Transplant Medicine, University Duisburg-Essen, Essen, Germany.
²⁶ Pediatric Gastroenterology, University of Minnesota Medical School, Minneapolis, MN, USA.
²⁷ Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.
²⁸ University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
²⁹ Reference Center for Inherited Metabolic Diseases, Jeanne de Flandres Hospital, Lille, France.
³⁰ Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
³¹ Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³² Department of Clinical Genetics and Molecular Genetics, Hospital Vall d'Hebron, Barcelona, Spain.
³³ CellNetworks, Bioquant, Heidelberg University, Heidelberg, Germany.
³⁴ Biochemie Zentrum Heidelberg (BZH), Heidelberg University, Heidelberg, Germany.
³⁵ Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. Dominic.Lenz@med.uni-heidelberg.de.

PMID: 31761904
DOI: 10.1038/s41436-019-0698-4

Abstract

Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis.

Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods.

Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH).

Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

Keywords: NBAS; RALF; SOPH syndrome; acute liver failure; infantile liver failure syndrome type 2.

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References

1. Maksimova N, Hara K, Nikolaeva I, et al. Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huet anomaly. J Med Genet. 2010;47:538–548. - PubMed - PMC
1. Haack TB, Staufner C, Kopke MG, et al. Biallelic mutations in NBAS cause recurrent acute liver failure with onset in infancy. Am J Hum Genet. 2015;97:163–169. - PubMed - PMC
1. Staufner C, Haack TB, Kopke MG, et al. Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts. J Inherit Metab Dis. 2016;39:3–16. - PubMed
1. Kortum F, Marquardt I, Alawi M, et al. Acute liver failure meets SOPH syndrome: a case report on an intermediate phenotype. Pediatrics. 2017;139:e20160550. - PubMed
1. Segarra NG, Ballhausen D, Crawford H, et al. NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina. Am J Hum Genet A. 2015;167A:2902–2912.

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Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients

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Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients

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