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Journal Articles Hepatology Year : 2023

Genetic landscape of pediatric acute liver failure of indeterminate origin

Dominic Lenz , Lea Schlieben , Masaru Shimura , Alyssa Bianzano , Dmitrii Smirnov , Robert Kopajtich , Riccardo Berutti , Rüdiger Adam , Denise Aldrian , Ivo Baric , Ulrich Baumann , Neslihan Eksi Bozbulut , Melanie Brugger , Theresa Brunet , Philip Bufler , Birutė Burnytė , Pier Luigi Calvo , Ellen Crushell , Buket Dalgıç , Anibh Das , Antal Dezsőfi , Felix Distelmaier , Alexander Fichtner , Peter Freisinger , Sven Garbade , Harald Gaspar , Louise Goujon , Nedim Hadzic , Steffen Hartleif , Bianca Hegen , Maja Hempel , Stephan Henning , Andre Hoerning , Roderick Houwen , Joanne Hughes , Raffaele Iorio , Katarzyna Iwanicka-Pronicka , Martin Jankofsky , Norman Junge , Ino Kanavaki , Aydan Kansu , Sonja Kaspar , Simone Kathemann , Deidre Kelly , Ceyda Tuna Kırsaçlıoğlu , Birgit Knoppke , Martina Kohl , Heike Kölbel , Stefan Kölker , Vassiliki Konstantopoulou , Tatiana Krylova , Zarife Kuloğlu , Alice Kuster (1, 2) , Martin Laass , Elke Lainka , Eberhard Lurz , Hanna Mandel , Katharina Mayerhanser , Johannes Mayr , Patrick Mckiernan , Patricia Mclean , Valerie Mclin , Karine Mention , Hanna Müller , Laurent Pasquier , Martin Pavlov , Natalia Pechatnikova , Bianca Peters , Danijela Petković Ramadža , Dorota Piekutowska-Abramczuk , Denisa Pilic , Sanjay Rajwal , Nathalie Rock , Agnès Roetig , René Santer , Wilfried Schenk , Natalia Semenova , Christiane Sokollik , Ekkehard Sturm , Robert Taylor , Eva Tschiedel , Vaidotas Urbonas , Roser Urreizti , Jan Vermehren , Jerry Vockley , Georg-Friedrich Vogel , Matias Wagner , Wendy van der Woerd , Saskia Wortmann , Ekaterina Zakharova , Georg Friedrich Hoffmann , Thomas Meitinger , Kei Murayama , Christian Staufner , Holger Prokisch
Dominic Lenz
  • Function : Author
Lea Schlieben
  • Function : Author
Masaru Shimura
  • Function : Author
Alyssa Bianzano
  • Function : Author
Dmitrii Smirnov
  • Function : Author
Robert Kopajtich
  • Function : Author
Riccardo Berutti
  • Function : Author
Rüdiger Adam
  • Function : Author
Denise Aldrian
  • Function : Author
Ivo Baric
  • Function : Author
Ulrich Baumann
  • Function : Author
Neslihan Eksi Bozbulut
  • Function : Author
Melanie Brugger
  • Function : Author
Theresa Brunet
  • Function : Author
Philip Bufler
  • Function : Author
Birutė Burnytė
  • Function : Author
Pier Luigi Calvo
  • Function : Author
Ellen Crushell
  • Function : Author
Buket Dalgıç
  • Function : Author
Anibh Das
  • Function : Author
Antal Dezsőfi
  • Function : Author
Felix Distelmaier
  • Function : Author
Alexander Fichtner
  • Function : Author
Peter Freisinger
  • Function : Author
Sven Garbade
  • Function : Author
Harald Gaspar
  • Function : Author
Louise Goujon
  • Function : Author
Nedim Hadzic
  • Function : Author
Steffen Hartleif
  • Function : Author
Bianca Hegen
  • Function : Author
Maja Hempel
  • Function : Author
Stephan Henning
  • Function : Author
Andre Hoerning
  • Function : Author
Roderick Houwen
  • Function : Author
Joanne Hughes
  • Function : Author
Raffaele Iorio
  • Function : Author
Katarzyna Iwanicka-Pronicka
  • Function : Author
Martin Jankofsky
  • Function : Author
Norman Junge
  • Function : Author
Ino Kanavaki
  • Function : Author
Aydan Kansu
  • Function : Author
Sonja Kaspar
  • Function : Author
Simone Kathemann
  • Function : Author
Deidre Kelly
  • Function : Author
Ceyda Tuna Kırsaçlıoğlu
  • Function : Author
Birgit Knoppke
  • Function : Author
Martina Kohl
  • Function : Author
Heike Kölbel
  • Function : Author
Stefan Kölker
  • Function : Author
Vassiliki Konstantopoulou
  • Function : Author
Tatiana Krylova
  • Function : Author
Zarife Kuloğlu
  • Function : Author
Martin Laass
  • Function : Author
Elke Lainka
  • Function : Author
Eberhard Lurz
  • Function : Author
Hanna Mandel
  • Function : Author
Katharina Mayerhanser
  • Function : Author
Johannes Mayr
  • Function : Author
Patrick Mckiernan
  • Function : Author
Patricia Mclean
  • Function : Author
Valerie Mclin
  • Function : Author
Karine Mention
  • Function : Author
Hanna Müller
  • Function : Author
Laurent Pasquier
  • Function : Author
Martin Pavlov
  • Function : Author
Natalia Pechatnikova
  • Function : Author
Bianca Peters
  • Function : Author
Danijela Petković Ramadža
  • Function : Author
Dorota Piekutowska-Abramczuk
  • Function : Author
Denisa Pilic
  • Function : Author
Sanjay Rajwal
  • Function : Author
Nathalie Rock
  • Function : Author
Agnès Roetig
  • Function : Author
René Santer
  • Function : Author
Wilfried Schenk
  • Function : Author
Natalia Semenova
  • Function : Author
Christiane Sokollik
  • Function : Author
Ekkehard Sturm
  • Function : Author
Robert Taylor
  • Function : Author
Eva Tschiedel
  • Function : Author
Vaidotas Urbonas
  • Function : Author
Roser Urreizti
  • Function : Author
Jan Vermehren
  • Function : Author
Jerry Vockley
  • Function : Author
Georg-Friedrich Vogel
  • Function : Author
Matias Wagner
  • Function : Author
Wendy van der Woerd
  • Function : Author
Saskia Wortmann
  • Function : Author
Ekaterina Zakharova
  • Function : Author
Georg Friedrich Hoffmann
  • Function : Author
Thomas Meitinger
  • Function : Author
Kei Murayama
  • Function : Author
Christian Staufner
  • Function : Author
Holger Prokisch
  • Function : Author

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.
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Dates and versions

hal-04417970 , version 1 (25-01-2024)

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Dominic Lenz, Lea Schlieben, Masaru Shimura, Alyssa Bianzano, Dmitrii Smirnov, et al.. Genetic landscape of pediatric acute liver failure of indeterminate origin. Hepatology, 2023, ⟨10.1097/HEP.0000000000000684⟩. ⟨hal-04417970⟩
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