Christian Staufner1, Bianca Peters1, Matias Wagner2,3,4, 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 Kopajtich2,3, 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 Riedhammer2,3,30, René Santer31, Irene Valenzuela Palafoll32, Jerry Vockley28, Dominik S Westphal2,3, Arnaud Wiedemann17, Saskia B Wortmann2,3,27, Gaurav D Diwan33,34, Robert B Russell33,34, Holger Prokisch2,3, Sven F Garbade1, Stefan Kölker1, Georg F Hoffmann1, Dominic Lenz35. 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.
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.
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.
Authors: Christian Staufner; Tobias B Haack; Marlies G Köpke; Beate K Straub; Stefan Kölker; Christian Thiel; Peter Freisinger; Ivo Baric; Patrick J McKiernan; Nicola Dikow; Inga Harting; Flemming Beisse; Peter Burgard; Urania Kotzaeridou; Dominic Lenz; Joachim Kühr; Urban Himbert; Robert W Taylor; Felix Distelmaier; Jerry Vockley; Lina Ghaloul-Gonzalez; John A Ozolek; Johannes Zschocke; Alice Kuster; Anke Dick; Anib M Das; Thomas Wieland; Caterina Terrile; Tim M Strom; Thomas Meitinger; Holger Prokisch; Georg F Hoffmann Journal: J Inherit Metab Dis Date: 2015-11-05 Impact factor: 4.982
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Authors: Pier Luigi Calvo; Francesco Tandoi; Tobias B Haak; Andrea Brunati; Michele Pinon; Dominic Dell Olio; Renato Romagnoli; Marco Spada Journal: Ital J Pediatr Date: 2017-09-25 Impact factor: 2.638
Authors: Mohammed Y Hasosah; Alaa I Iskandarani; Ayman I Shawli; Ashraf F Alsahafi; Ghassan A Sukkar; Mansour A Qurashi Journal: Saudi J Gastroenterol Date: 2017 May-Jun Impact factor: 2.485
Authors: Jean Tori Pantel; Nurulhuda Hajjir; Magdalena Danyel; Jonas Elsner; Angela Teresa Abad-Perez; Peter Hansen; Stefan Mundlos; Malte Spielmann; Denise Horn; Claus-Eric Ott; Martin Atta Mensah Journal: J Med Internet Res Date: 2020-10-22 Impact factor: 5.428
Authors: J A Mayr; R G Feichtinger; M T Achleitner; K Brugger; K Kutsam; J Spenger; J Koch; P Hofbauer; F B Lagler; W Sperl; D Weghuber; S B Wortmann Journal: Monatsschr Kinderheilkd Date: 2021-07-29 Impact factor: 0.323