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Genetic landscape of pediatric acute liver failure of indeterminate origin
Dominic Lenz1, Lea D Schlieben2,3, Masaru Shimura3,4
1Heidelberg University, Medical Faculty, University Hospital Heidelberg, Center for Child and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany.
Insights
Genetic testing via whole-exome sequencing (WES) identified the cause in 37% of pediatric acute liver failure (PALF) cases of unknown origin. This highlights the importance of genetic evaluation for diagnosing rare liver diseases in children.
Area of Science:
- Genetics
- Pediatrics
- Hepatology
Background:
- Pediatric acute liver failure (PALF) is a critical condition with elusive etiologies in up to 50% of cases.
- Viral infections and inherited metabolic diseases are known causes, but many cases remain indeterminate, complicating management and liver transplantation decisions.
Purpose of the Study:
- To investigate the diagnostic yield of whole-exome sequencing (WES) in pediatric patients with indeterminate PALF.
- To analyze phenotypic and biochemical markers associated with genetic causes of PALF.
Main Methods:
- An international, multicenter observational study analyzing 260 pediatric patients (0-18 years) with indeterminate PALF using WES.
- Systematic retrieval and analysis of clinical and biochemical phenotype data.
Main Results:
- WES established a genetic diagnosis in 37% of cases (97/260), with higher yields in infants (41%) and recurrent PALF (64%).
- Thirty-six disease genes were identified, with NBAS, MPV17, and DGUOK being the most frequent. Mitochondrial diseases, vesicular trafficking disorders, and aminoacyl-tRNA synthetase deficiencies were common categories.
- One-third of patients experienced a fatal outcome, and 56 underwent liver transplantation.
Conclusions:
- Genetic factors significantly contribute to PALF of indeterminate origin, revealing an expanding spectrum of disease entities.
- The high diagnostic rate supports the use of WES, and potentially rapid genome sequencing, in PALF diagnostics due to treatment implications.
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.
