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Observational Study
. 2024 May 1;79(5):1075-1087.
doi: 10.1097/HEP.0000000000000684. Epub 2023 Nov 16.

Genetic landscape of pediatric acute liver failure of indeterminate origin

Dominic Lenz  1 , Lea D Schlieben  2   3 , Masaru Shimura  3   4 , Alyssa Bianzano  1 , Dmitrii Smirnov  2   3 , Robert Kopajtich  2   3 , Riccardo Berutti  2   3 , Rüdiger Adam  5 , Denise Aldrian  6 , Ivo Baric  7 , Ulrich Baumann  8 , Neslihan E Bozbulut  9 , Melanie Brugger  2 , Theresa Brunet  2 , Philip Bufler  10 , Birutė Burnytė  11 , Pier L Calvo  12 , Ellen Crushell  13 , Buket Dalgiç  9 , Anibh M Das  14 , Antal Dezsőfi  15 , Felix Distelmaier  16 , Alexander Fichtner  1 , Peter Freisinger  17 , Sven F Garbade  1 , Harald Gaspar  18 , Louise Goujon  19 , Nedim Hadzic  20 , Steffen Hartleif  21 , Bianca Hegen  22 , Maja Hempel  23   24 , Stephan Henning  10 , Andre Hoerning  25 , Roderick Houwen  26 , Joanne Hughes  27 , Raffaele Iorio  28 , Katarzyna Iwanicka-Pronicka  29 , Martin Jankofsky  22 , Norman Junge  8 , Ino Kanavaki  30 , Aydan Kansu  31 , Sonja Kaspar  25 , Simone Kathemann  32 , Deidre Kelly  33 , Ceyda T Kirsaçlioğlu  31 , Birgit Knoppke  34 , Martina Kohl  35 , Heike Kölbel  36 , Stefan Kölker  1 , Vassiliki Konstantopoulou  37 , Tatiana Krylova  38 , Zarife Kuloğlu  31 , Alice Kuster  39 , Martin W Laass  40 , Elke Lainka  32 , Eberhard Lurz  41 , Hanna Mandel  42 , Katharina Mayerhanser  2 , Johannes A Mayr  43 , Patrick McKiernan  44 , Patricia McClean  45 , Valerie McLin  46 , Karine Mention  47 , Hanna Müller  48 , Laurent Pasquier  19 , Martin Pavlov  2   3 , Natalia Pechatnikova  49 , Bianca Peters  1 , Danijela Petković Ramadža  7 , Dorota Piekutowska-Abramczuk  29 , Denisa Pilic  32 , Sanjay Rajwal  46 , Nathalie Rock  46 , Agnès Roetig  50 , René Santer  22 , Wilfried Schenk  51 , Natalia Semenova  38 , Christiane Sokollik  52 , Ekkehard Sturm  21 , Robert W Taylor  53 , Eva Tschiedel  54 , Vaidotas Urbonas  11 , Roser Urreizti  55 , Jan Vermehren  34 , Jerry Vockley  44 , Georg-Friedrich Vogel  6   56 , Matias Wagner  2 , Wendy van der Woerd  26 , Saskia B Wortmann  43 , Ekaterina Zakharova  38 , Georg F Hoffmann  1 , Thomas Meitinger  2 , Kei Murayama  4 , Christian Staufner  1 , Holger Prokisch  2   3
Affiliations
Observational Study

Genetic landscape of pediatric acute liver failure of indeterminate origin

Dominic Lenz et al. Hepatology. .

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.

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Conflict of interest statement

Ulrich Baumann consults, advises, is on the speakers’ bureau, and received grants from Albireo and Mirum. He advises and received grants from Alexion and Astellas. He consults for Vivet. Pier Luigi Calvo advises Albireo/Ipsen, Mirum, and Nestle. Felix Distelmaier received grants from Danone, DFG, Elterninitiative Kinderkrebsklinik E.V., Margarete-Breuer Stiftung, PTC Therapeutics, Santhera, and TANGO2 Research Foundation. Elke Lainka advises Albireo and Mirum. Eberhard Lurz consults, advises, and is on the speakers’ bureau for Albireo, Mirum, Nutricia, and Takeda. The remaining authors have no conflicts to report.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Geographical origin, clinical phenotypes, and affected organ systems. (A) Geographic origin: the number of patients recruited within the different countries is indicated by color. (B) Ancestry prediction based on WES data. (C) Frequency of phenotypic abnormalities within the whole cohort using the HPO. HPO terms with a frequency of 20 and higher are displayed. The exact INR values were not available for all cases, however, for all patients with available INR information, INR levels were abnormally elevated. All frequencies are shown in absolute numbers. Missing data may have led to low numbers in some of the items (eg, cholestasis, conjugated hyperbilirubinemia). Abbreviations: AFR, African; EAS, east Asian; EUR, European; HPO, Human Phenotype Ontology; SAS, south Asian; WES, whole-exome sequencing.
FIGURE 2
FIGURE 2
Biochemical characterization of the cohort. Laboratory characterization of ALF and RALF including aspartate aminotransferase, alanine aminotransferase, liver function (INR), total bilirubin as well as direct bilirubin using violin plots. Bold dots indicate the median, bars indicate the 25th to 75th percentile; green dots represent values within the reference range for normal values according to a consensus of Deutsche Gesellschaft für Klinische Chemie und Laboratoriumsmedizin and Verband der Diagnostika- und Diagnostikageräte-Hersteller. *p≤0.05 **p≤0.01 ***p≤0.001 ****p≤0.0001 by Wilcoxon test. Abbreviations: ALF, acute liver failure; ALT, alanine aminotransferase; AST, aspartate aminotransferase; RALF, recurrent acute liver failure.
FIGURE 3
FIGURE 3
Outcome of patients with pediatric acute liver failure. (A) Patient and native liver survival. (B) Timeline for age at first ALF in years. (C) Timeline for age of death after the first ALF in years. (D) Kaplan-Meier plot for the native liver survival after the first ALF stratified by the clinical phenotype in months. p-value calculation by log-rank test. (E) Kaplan-Meier plot for the native liver survival after the first ALF stratified by the age of onset. Abbreviations: ALF, acute liver failure; RALF, recurrent acute liver failure.
FIGURE 4
FIGURE 4
Molecular etiology of pediatric acute liver failure. (A) Genetic spectrum of pediatric acute liver failure; (B) diagnostic yield, stratified by ALF vs. RALF; (C) age of onset stratified by disease groups; and (D) native liver survival after first ALF stratified by the 2 most frequent disease groups. Abbreviations: ALF, acute liver failure; RALF, recurrent acute liver failure; WES, whole-exome sequencing.
FIGURE 5
FIGURE 5
(A) Mitochondrial disease genes causing pediatric acute liver failure. (B) Disorders of vesicular trafficking and aminoacyl-tRNA synthetase deficiency (box) leading to pediatric acute liver failure. Genes with pathogenic variants that have been identified in cases within this study are shown in bold.
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Comment in

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