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Genetic landscape of pediatric acute liver failure of indeterminate origin

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

In: HEPATOLOGY, Vol. 79, No. 5, 01.05.2024, p. 1075-1087.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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, Burnytė, B, Calvo, PL, Crushell, E, Dalgıç, B, Das, AM, Dezsőfi, A, Distelmaier, F, Fichtner, A, Freisinger, P, Garbade, SF, Gaspar, H, Goujon, L, Hadzic, N, Hartleif, S, Hegen, B, Hempel, M, Henning, S, Hoerning, A, Houwen, R, Hughes, J, Iorio, R, Iwanicka-Pronicka, K, Jankofsky, M, Junge, N, Kanavaki, I, Kansu, A, Kaspar, S, Kathemann, S, Kelly, D, Kırsaçlıoğlu, CT, Knoppke, B, Kohl, M, Kölbel, H, Kölker, S, Konstantopoulou, V, Krylova, T, Kuloğlu, Z, Kuster, A, Laass, MW, Lainka, E, Lurz, E, Mandel, H, Mayerhanser, K, Mayr, JA, McKiernan, P, McLean, P, McLin, V, Mention, K, Müller, H, Pasquier, L, Pavlov, M, Pechatnikova, N, Peters, B, Petković Ramadža, 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, G-F, Wagner, M, van der Woerd, W, Wortmann, SB, Zakharova, E, Hoffmann, GF, Meitinger, T, Murayama, K, Staufner, C & Prokisch, H 2024, 'Genetic landscape of pediatric acute liver failure of indeterminate origin', HEPATOLOGY, vol. 79, no. 5, pp. 1075-1087. https://doi.org/10.1097/HEP.0000000000000684

APA

Lenz, D., Schlieben, L. D., Shimura, M., Bianzano, A., Smirnov, D., Kopajtich, R., Berutti, R., Adam, R., Aldrian, D., Baric, I., Baumann, U., Bozbulut, N. E., Brugger, M., Brunet, T., Bufler, P., Burnytė, B., Calvo, P. L., Crushell, E., Dalgıç, B., ... 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

Vancouver

Lenz D, Schlieben LD, Shimura M, Bianzano A, Smirnov D, Kopajtich R et al. Genetic landscape of pediatric acute liver failure of indeterminate origin. HEPATOLOGY. 2024 May 1;79(5):1075-1087. https://doi.org/10.1097/HEP.0000000000000684

Bibtex

@article{177e1e148e2143b181136c79f2feaab9,
title = "Genetic landscape of pediatric acute liver failure of indeterminate origin",
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.",
author = "Dominic Lenz and Schlieben, {Lea D} and Masaru Shimura and Alyssa Bianzano and Dmitrii Smirnov and Robert Kopajtich and Riccardo Berutti and R{\"u}diger Adam and Denise Aldrian and Ivo Baric and Ulrich Baumann and Bozbulut, {Neslihan Eksi} and Melanie Brugger and Theresa Brunet and Philip Bufler and Birutė Burnytė and Calvo, {Pier Luigi} and Ellen Crushell and Buket Dalgı{\c c} and Das, {Anibh M} and Antal Dezs{\H o}fi and Felix Distelmaier and Alexander Fichtner and Peter Freisinger and Garbade, {Sven F} and Harald Gaspar and Louise Goujon and Nedim Hadzic and Steffen Hartleif and Bianca Hegen and Maja Hempel and Stephan Henning and Andre Hoerning and Roderick Houwen and Joanne Hughes and Raffaele Iorio and Katarzyna Iwanicka-Pronicka and Martin Jankofsky and Norman Junge and Ino Kanavaki and Aydan Kansu and Sonja Kaspar and Simone Kathemann and Deidre Kelly and Kırsa{\c c}lıoğlu, {Ceyda Tuna} and Birgit Knoppke and Martina Kohl and Heike K{\"o}lbel and Stefan K{\"o}lker and Vassiliki Konstantopoulou and Tatiana Krylova and Zarife Kuloğlu and Alice Kuster and Laass, {Martin W} and Elke Lainka and Eberhard Lurz and Hanna Mandel and Katharina Mayerhanser and Mayr, {Johannes A} and Patrick McKiernan and Patricia McLean and Valerie McLin and Karine Mention and Hanna M{\"u}ller and Laurent Pasquier and Martin Pavlov and Natalia Pechatnikova and Bianca Peters and {Petkovi{\'c} Ramad{\v z}a}, Danijela and Dorota Piekutowska-Abramczuk and Denisa Pilic and Sanjay Rajwal and Nathalie Rock and Agn{\`e}s Roetig and Ren{\'e} Santer and Wilfried Schenk and Natalia Semenova and Christiane Sokollik and Ekkehard Sturm and Taylor, {Robert W} and Eva Tschiedel and Vaidotas Urbonas and Roser Urreizti and Jan Vermehren and Jerry Vockley and Georg-Friedrich Vogel and Matias Wagner and {van der Woerd}, Wendy and Wortmann, {Saskia B} and Ekaterina Zakharova and Hoffmann, {Georg Friedrich} and Thomas Meitinger and Kei Murayama and Christian Staufner and Holger Prokisch",
note = "Copyright {\textcopyright} 2023 The Author(s). Published by Wolters Kluwer Health, Inc.",
year = "2024",
month = may,
day = "1",
doi = "10.1097/HEP.0000000000000684",
language = "English",
volume = "79",
pages = "1075--1087",
journal = "HEPATOLOGY",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "5",

}

RIS

TY - JOUR

T1 - Genetic landscape of pediatric acute liver failure of indeterminate origin

AU - Lenz, Dominic

AU - Schlieben, Lea D

AU - Shimura, Masaru

AU - Bianzano, Alyssa

AU - Smirnov, Dmitrii

AU - Kopajtich, Robert

AU - Berutti, Riccardo

AU - Adam, Rüdiger

AU - Aldrian, Denise

AU - Baric, Ivo

AU - Baumann, Ulrich

AU - Bozbulut, Neslihan Eksi

AU - Brugger, Melanie

AU - Brunet, Theresa

AU - Bufler, Philip

AU - Burnytė, Birutė

AU - Calvo, Pier Luigi

AU - Crushell, Ellen

AU - Dalgıç, Buket

AU - Das, Anibh M

AU - Dezsőfi, Antal

AU - Distelmaier, Felix

AU - Fichtner, Alexander

AU - Freisinger, Peter

AU - Garbade, Sven F

AU - Gaspar, Harald

AU - Goujon, Louise

AU - Hadzic, Nedim

AU - Hartleif, Steffen

AU - Hegen, Bianca

AU - Hempel, Maja

AU - Henning, Stephan

AU - Hoerning, Andre

AU - Houwen, Roderick

AU - Hughes, Joanne

AU - Iorio, Raffaele

AU - Iwanicka-Pronicka, Katarzyna

AU - Jankofsky, Martin

AU - Junge, Norman

AU - Kanavaki, Ino

AU - Kansu, Aydan

AU - Kaspar, Sonja

AU - Kathemann, Simone

AU - Kelly, Deidre

AU - Kırsaçlıoğlu, Ceyda Tuna

AU - Knoppke, Birgit

AU - Kohl, Martina

AU - Kölbel, Heike

AU - Kölker, Stefan

AU - Konstantopoulou, Vassiliki

AU - Krylova, Tatiana

AU - Kuloğlu, Zarife

AU - Kuster, Alice

AU - Laass, Martin W

AU - Lainka, Elke

AU - Lurz, Eberhard

AU - Mandel, Hanna

AU - Mayerhanser, Katharina

AU - Mayr, Johannes A

AU - McKiernan, Patrick

AU - McLean, Patricia

AU - McLin, Valerie

AU - Mention, Karine

AU - Müller, Hanna

AU - Pasquier, Laurent

AU - Pavlov, Martin

AU - Pechatnikova, Natalia

AU - Peters, Bianca

AU - Petković Ramadža, Danijela

AU - Piekutowska-Abramczuk, Dorota

AU - Pilic, Denisa

AU - Rajwal, Sanjay

AU - Rock, Nathalie

AU - Roetig, Agnès

AU - Santer, René

AU - Schenk, Wilfried

AU - Semenova, Natalia

AU - Sokollik, Christiane

AU - Sturm, Ekkehard

AU - Taylor, Robert W

AU - Tschiedel, Eva

AU - Urbonas, Vaidotas

AU - Urreizti, Roser

AU - Vermehren, Jan

AU - Vockley, Jerry

AU - Vogel, Georg-Friedrich

AU - Wagner, Matias

AU - van der Woerd, Wendy

AU - Wortmann, Saskia B

AU - Zakharova, Ekaterina

AU - Hoffmann, Georg Friedrich

AU - Meitinger, Thomas

AU - Murayama, Kei

AU - Staufner, Christian

AU - Prokisch, Holger

N1 - Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.

PY - 2024/5/1

Y1 - 2024/5/1

N2 - 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.

AB - 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.

U2 - 10.1097/HEP.0000000000000684

DO - 10.1097/HEP.0000000000000684

M3 - SCORING: Journal article

C2 - 37976411

VL - 79

SP - 1075

EP - 1087

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 5

ER -