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.

中文翻译：

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不明原因的小儿急性肝衰竭的遗传景观。

背景 目的 小儿急性肝衰竭（PALF）是一种危及生命的疾病。在欧洲，主要原因是病毒感染（12-16%）和遗传性代谢疾病（14-28%）。然而，在高达 50% 的病例中，其根本病因仍然难以捉摸，这给临床治疗（包括肝移植）带来了挑战。我们系统地研究了通过全外显子组测序 (WES) 进行遗传评估的不确定 PALF 病例，并分析了表型和生化标记，以及 WES 在这种情况下的诊断率。方法 在这项国际多中心观察性研究中，通过 WES 分析了不确定 PALF 的患者（0-18 岁）。检索并系统分析了临床和生化表型的数据。结果 2011年至2022年间，总共招募了来自19个国家的260名不确定的PALF患者，其中59名患有复发性PALF（RALF）。WES 对 37% 的病例 (97/260) 进行了基因诊断。出生一年内患有 PALF 的儿童（46%）和患有 RALF 的儿童（64%）的诊断率最高。鉴定出 36 个不同的疾病基因。NBAS (n=20)、MPV17 (n=8) 和 DGUOK (n=7) 缺陷是最常见的发现。分类时，最常见的是线粒体疾病（45%）、囊泡运输障碍（28%）和胞质氨酰-tRNA 合成酶缺陷（10%）。三分之一的患者死亡。56 名患者接受了肝移植。结论 这项研究阐明了遗传原因对不明原因 PALF 的重要贡献，并且疾病种类不断增加。高比例的诊断病例​​和潜在的治疗影响支持外显子组或未来 PALF 诊断中的快速基因组测序。