Genetic landscape of pediatric acute liver failure of indeterminate origin-Reference-Cited by-同舟云学术

Genetic landscape of pediatric acute liver failure of indeterminate origin

Published:2023-11-17 Issue: Volume: Page:
ISSN:0270-9139
Container-title:Hepatology
language:en
Short-container-title:

Author:

Lenz Dominic¹,Schlieben Lea D.²³,Shimura Masaru³⁴,Bianzano Alyssa¹,Smirnov Dmitrii²³,Kopajtich Robert²³,Berutti Riccardo²³,Adam Rüdiger⁵,Aldrian Denise⁶,Baric Ivo⁷,Baumann Ulrich⁸,Bozbulut Neslihan Eksi⁹,Brugger Melanie²,Brunet Theresa²,Bufler Philip¹⁰,Burnytė Birutė¹¹,Calvo Pier Luigi¹²,Crushell Ellen¹³,Dalgıç Buket⁹,Das Anibh M.¹⁴,Dezsőfi Antal¹⁵,Distelmaier Felix¹⁶,Fichtner Alexander¹,Freisinger Peter¹⁷,Garbade Sven F.¹,Gaspar Harald¹⁸,Goujon Louise¹⁹,Hadzic Nedim²⁰,Hartleif Steffen²¹,Hegen Bianca²²,Hempel Maja²³²⁴,Henning Stephan¹⁰,Hoerning Andre²⁵,Houwen Roderick²⁶,Hughes Joanne²⁷,Iorio Raffaele²⁸,Iwanicka-Pronicka Katarzyna²⁹,Jankofsky Martin²²,Junge Norman⁸,Kanavaki Ino³⁰,Kansu Aydan³¹,Kaspar Sonja²⁵,Kathemann Simone³²,Kelly Deidre³³,Kırsaçlıoğlu Ceyda Tuna³¹,Knoppke Birgit³⁴,Kohl Martina³⁵,Kölbel Heike³⁶,Kölker Stefan¹,Konstantopoulou Vassiliki³⁷,Krylova Tatiana³⁸,Kuloğlu Zarife³¹,Kuster Alice³⁹,Laass Martin W.⁴⁰,Lainka Elke³²,Lurz Eberhard⁴¹,Mandel Hanna⁴²,Mayerhanser Katharina²,Mayr Johannes A.⁴³,McKiernan Patrick⁴⁴,McLean Patricia⁴⁵,McLin Valerie⁴⁶,Mention Karine⁴⁷,Müller Hanna⁴⁸,Pasquier Laurent¹⁹,Pavlov Martin²³,Pechatnikova Natalia⁴⁹,Peters Bianca¹,Petković Ramadža Danijela⁷,Piekutowska-Abramczuk Dorota²⁹,Pilic Denisa³²,Rajwal Sanjay⁴⁶,Rock Nathalie⁴⁶,Roetig Agnès⁵⁰,Santer René²²,Schenk Wilfried⁵¹,Semenova Natalia³⁸,Sokollik Christiane⁵²,Sturm Ekkehard²¹,Taylor Robert W.⁵³,Tschiedel Eva⁵⁴,Urbonas Vaidotas¹¹,Urreizti Roser⁵⁵,Vermehren Jan³⁴,Vockley Jerry⁴⁴,Vogel Georg-Friedrich⁶⁵⁶,Wagner Matias²,van der Woerd Wendy²⁶,Wortmann Saskia B.⁴³,Zakharova Ekaterina³⁸,Hoffmann Georg Friedrich¹,Meitinger Thomas²,Murayama Kei⁴,Staufner Christian¹,Prokisch Holger²³

Affiliation:

1. Division of Neuropaediatrics and Paediatric Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany

2. School of Medicine, Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

3. Institute of Neurogenomics, Computational Health Centre, Helmholtz Zentrum München, Neuherberg, Germany

4. Chiba Children’s Hospital, Centre for Medical Genetics and Department of Metabolism, Chiba, Japan

5. University Children’s Hospital; Paediatric Gastroenterology, Hepatology and Nutrition; Medical Faculty Mannheim; Heidelberg University; Mannheim, Germany

6. Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria

7. University Hospital Centre Zagreb, Department of Paediatrics and University of Zagreb, School of Medicine, Zagreb, Croatia

8. Division for Paediatric Gastroenterology and Hepatology, Department of Peadiatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany

9. Gazi University Faculty of Medicine, Department of Paediatric Gastroenterology, Ankara, Turkey

10. Charité - Universitätsmedizin Berlin, Department of Paediatric Gastroenterology, Nephrology and Metabolic Diseases, Berlin, Germany

11. Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania

12. Regina Margherita Children’s Hospital, Paediatic Gastroenterology Unit, Torino, Italy

13. National Centre for Inherited Metabolic Disorders, Children’s Health Ireland at Temple st, Dublin, Ireland

14. Hannover Medical School, Clinic for Paediatric Kidney, Liver, and Metabolic Diseases, Hannover, Germany

15. First Department of Paediatrics, Semmelweis University, Budapest, Hungary

16. University Children’s Hospital, Heinrich-Heine-University Düsseldorf, Department of General Paediatrics, Neonatology and Paediatric Cardiology, Düsseldorf, Germany

17. Hospital Reutlingen, Department of Paediatrics, Reutlingen, Germany

18. Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

19. CLAD Ouest CHU Hôpital Sud, CRMR Déficiences intellectuelles, Service de Génétique Médicale, Rennes, France

20. King’s College Hospital, Paediatric Liver, GI & Nutrition Centre, London, United Kingdom

21. Eberhard Karls University Tuebingen, Paediatric Gastroenterology and Hepatology, Tuebingen, Germany

22. University Medical Centre Hamburg-Eppendorf, Department of Paediatrics, Hamburg, Germany

23. University Hospital Heidelberg, Institute of Human Genetics, Heidelberg, Germany

24. University Medical Centre Hamburg-Eppendorf, Institute of Human Genetics, Hamburg

25. University Hospital Erlangen, Department of Paediatrics, Erlangen, Germany

26. Paediatric Gastroenterology, UMC Utrecht, Utrecht, The Netherlands

27. Children’s Health Ireland, Temple Street Hospital, Dublin, Ireland

28. University of Naples Federico II, Department of Translational Medical Sciences, Naples, Italy

29. Children’s Memorial Health Institute, Department of Medical Genetics, Warsaw, Poland

30. Department of Paediatric Gastroenterology, Hepatology and Nutrition, Third Department of Paediatrics, Attikon University General Hospital, National and Kapodistrian University of Athens, Athens, Greece

31. Ankara University, School of Medicine, Department of Paediatric Gastroenterology, Ankara, Turkey

32. University Hospital Essen, Department of Paediatrics II, Paediatric Gastroenterology, Hepatology and Liver Transplantation, Essen, Germany

33. Birmingham Children’s Hospital NHS Trust, Liver Unit, Birmingham, United Kingdom

34. University Hospital Regensburg, KUNO University Children’s Hospital, Regensburg, Germany

35. University Medical Centre Schleswig-Holstein, Department of General Paediatrics, Kiel, Germany

36. Department of Paediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro and Behavioral Sciences, University Duisburg-Essen, Essen, Germany

37. Medical University of Vienna, Department of Paediatrics and Adolescent Medicine, Vienna, Austria

38. Research Centre for Medical Genetics, Moscow, Russian Federation

39. University Hospital of Nantes, Department of Neurometabolism, Nantes, France

40. Department of Pediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

41. Department of Paediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany

42. Rambam Medical Centre, Meyer Children’s Hospital, Department of Paediatrics, Metabolic Unit, Haifa, Israel

43. University Children’s Hospital, Paracelsus Medical University Salzburg, Salzburg, Austria

44. University of Pittsburgh and Children’s Hospital of Pittsburgh of UPMC, Pittsburgh Liver Research Centre, Pittsburgh, PA, United States

45. Children’s Liver Unit, Leeds Children’s Hospital, Leeds, UK

46. Swiss Paediatric Liver Centre, Paediatric Gastroenterology, Hepatology and Nutrition Unit, Division of Paediatric Subspecialities, Department of Paediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland

47. Jeanne de Flandres Hospital, Reference Centre for Inherited Metabolic Diseases, Lille, France

48. Division of Neonatology and Paediatric Intensive Care, Department of Paediatrics, University Hospital Marburg, Marburg, Germany

49. Morozov Children’s City Clinical Hospital of the Moscow City Healthcare Department, Moscow

50. University Paris Cité, Imagine Institute, Laboratory of Genetics of Mitochondrial Diseases, INSERM UMR 1163, Paris, France

51. Department of Paediatrics, university hospital Augsburg, Augsburg, Germany

52. Division of Paediatric Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

53. Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom

54. Department of Paediatrics I, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

55. Clinical Biochemistry Department, Hospital Sant Joan de Déu, IRSJD, Esplugues de Llobregat, Barcelona, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)- Instituto de Salud Carlos III, Spain

56. Institute of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria

Abstract

Background & Aims: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, main causes are viral infections (12-16%) and inherited metabolic diseases (14-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. Methods: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. Results: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF (RALF). WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (46%), and in children with RALF (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8) and DGUOK (n=7) were the most frequent findings. When categorizing, most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%) and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplants. Conclusion: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Hepatology

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