Genetic landscape of pediatric acute liver failure of indeterminate origin.

Lenz D, Schlieben LD, Shimura M, Bianzano A, Smirnov D, Kopajtich R, Berutti R, Adam R, Aldrian D, Baric I, Baumann U, Bozbulut NE, Brugger M, Brunet T, Bufler P, Burnyte B, Calvo PL, Crushell E, Dalgic B, Das AM, Dezsofi A, Distelmaier F, Fichtner A, Freisinger P, Garbade SF, Gaspar H, Goujon L, Hadzic N, Hartleif S, Hegen B, Hempel M, Henning S, Hörning A, Houwen R, Hughes J, Iorio R, Iwanicka-Pronicka K, Jankofsky M, Junge N, Kanavaki I, Kansu A, Kaspar S, Kathemann S, Kelly D, Kirsaclioglu CT, Knoppke B, Kohl M, Kolbel H, Kolker S, Konstantopoulou V, Krylova T, Kuloglu Z, Kuster A, Laass MW, Lainka E, Lurz E, Mandel H, Mayerhanser K, Mayr JA, McKiernan P, McClean P, McLin V, Mention K, Muller H, Pasquier L, Pavlov M, Pechatnikova N, Peters B, Petkovic Ramadza D, Piekutowska-Abramczuk D, Pilic D, Rajwal S, Rock N, Roetig A, Santer R, Schenk W, Semenova N, Sokollik C, Sturm E, Taylor RW, Tschiedel E, Urbonas V, Urreizti R, Vermehren J, Vockley J, Vogel GF, Wagner M, Van Der Woerd W, Wortmann SB, Zakharova E, Hoffmann GF, Meitinger T, Murayama K, Staufner C, Prokisch H (2024)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2024

Journal

Book Volume: 79

Pages Range: 1075-1087

Journal Issue: 5

DOI: 10.1097/HEP.0000000000000684

Abstract

BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the 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. APPROACH AND RESULTS: 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. 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 (41%), and in children with recurrent acute liver failure (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, the 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 transplantation. CONCLUSIONS: 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.

Authors with CRIS profile

Involved external institutions

Rambam Health Care Campus Israel (IL) Medizinische Universität Innsbruck Austria (AT) Universitätsklinikum Heidelberg Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Gazi University Turkey (TR) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Research Centre for Medical Genetics Russian Federation (RU) Hospital Sant Joan de Déu Barcelona Spain (ES) Charité - Universitätsmedizin Berlin Germany (DE) Vilnius University / Vilniaus universitetas Lithuania (LT) Semmelweis University / Semmelweis Egyetem Hungary (HU) Kreiskliniken Reutlingen Germany (DE) King's College Hospital (KCH) United Kingdom (GB) Eberhard Karls Universität Tübingen Germany (DE) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Ankara University / Ankara Üniversitesi Turkey (TR) Universitätsklinikum Essen Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Universitätsklinikum Augsburg Germany (DE) Klinikum rechts der Isar Germany (DE) Ospedale Infantile "Regina Margherita" Italy (IT) Temple Street Children's University Hospital / Children's Health Ireland (CHI) Ireland (IE) Universitätsklinikum Düsseldorf Germany (DE) Inselspital, Universitätsspital Bern Switzerland (CH) Attikon Hospital / Πανεπιστημιακού Γενικού Νοσοκομείου "Αττικόν" Greece (GR) Birmingham Women's and Children's NHS Foundation Trust United Kingdom (GB) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Centre hospitalier universitaire de Rennes / CHU Rennes France (FR) University of Geneva / Université de Genève (UNIGE) Switzerland (CH) Université Sorbonne Paris Cité France (FR) Klinikum der Universität München (LMU Klinikum) Germany (DE) University of Pittsburgh Medical Center (UPMC) United States (USA) (US) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) France (FR) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) Universitätsklinikum Regensburg Germany (DE) Universitätskliniken Salzburg Austria (AT) Chiba Children's Hospital Japan (JP) Medizinische Universität Wien Austria (AT) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) France (FR) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Universität Duisburg-Essen (UDE) Germany (DE) Zagreb University Hospital Centre / Klinički bolnički centar Zagreb (KBC) Croatia (HR) Children's Memorial Health Institute / Instytut "Pomnik - Centrum Zdrowia Dziecka" Poland (PL) Wellcome Centre for Mitochondrial Research United Kingdom (GB) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Università degli Studi di Napoli Federico II Italy (IT) Leeds Teaching Hospitals NHS Trust United Kingdom (GB) Morozovskaya Children's City Clinical Hospital Russian Federation (RU)

How to cite

APA:

Lenz, D., Schlieben, L.D., Shimura, M., Bianzano, A., Smirnov, D., Kopajtich, R.,... Prokisch, H. (2024). Genetic landscape of pediatric acute liver failure of indeterminate origin. Hepatology, 79(5), 1075-1087. https://doi.org/10.1097/HEP.0000000000000684

MLA:

Lenz, Dominic, et al. "Genetic landscape of pediatric acute liver failure of indeterminate origin." Hepatology 79.5 (2024): 1075-1087.

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