INTRODUCTION The etiology of acute liver failure (ALF) remains an important prognostic factor. The Acute Liver Failure Study Group recently reported that 150 of 2,718 adult patients with ALF (5.5%) had an indeterminate etiology. Our aim was to use whole exome sequencing to identify genetic variants associated with phenotypic, biochemical, and histologic features among patients with indeterminate ALF. METHODS This effort has defined a cohort of well-pedigreed patients with indeterminate ALF; DNA samples extracted from whole blood samples were obtained from 26 respective patients with indeterminate ALF. These samples were kept at the Acute Liver Failure Study Group repository at the NIDDK, Bethesda. Whole exome sequencing and bioinformatics analysis were performed at the Mayo Clinic Center of Individualized Medicine in Rochester, MN. RESULTS Of the 26 patients, 8 survived spontaneously, 6 died, and 12 underwent a liver transplantation; all those transplanted were alive at 21 days after enrollment in the study. Twenty-two of the 26 patients presented as ALF. We found 12 variants associated with 11 genes. The most common variant was rs4940595 in the SERPINB11 gene which was found in 23 of the 26 patients. This variant had a stop codon; no reports of disorders have been associated with this variant. The next most commonly found variant was rs1135840 in the CYP2D6 gene; this mutation is a missense_variant and has been reported to be associated with hepatotoxicity of antituberculous therapy. None of our patients were receiving this therapy. We also found a significant asymmetric distribution of rs1800754 of the CYP2D7 gene and rs1135840 of the CYP2D6 gene between patients who survived spontaneously (75%) and those who died or underwent liver transplantation (30.5% and 25%, respectively). DISCUSSION We found 12 variants of 11 genes significantly associated with ALF among adults with indeterminate etiology. We also found a significant asymmetric distribution of 2 variants belonging to the CYP2D7 and CYP2D6 genes, respectively, between those who survived spontaneously and those who died or underwent liver transplantation. The 2 most common variants, rs4940595 and rs1135840, of the SERPINB11 and CYP2D6 genes, respectively, found in our patients with ALF have been described as potentially important in the adaptive response combating the emergence of infectious diseases and associated with hepatotoxicity of antituberculous therapy, respectively. Our findings need to be expanded to include more patients with indeterminate ALF as well as viral, drug toxicity, and autoimmune etiologies to determine whether our findings are associated with the specific etiology, indeterminate, or with the overall ALF syndrome itself.

中文翻译：

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一项初步研究显示，在26例不确定的急性肝功能衰竭患者中进行全基因组测序。

引言急性肝衰竭（ALF）的病因仍然是重要的预后因素。急性肝衰竭研究小组最近报告说，在2,718名ALF成人患者中，有150名（5.5％）病因不明。我们的目标是使用全外显子组测序来确定不确定的ALF患者中与表型，生化和组织学特征相关的遗传变异。方法：这项工作已经定义了一组具有明确地位的ALF的患者。从全血样本中提取的DNA样本分别来自26名不确定的ALF患者。这些样本保存在Bethesda NIDDK的急性肝衰竭研究小组资料库中。整个外显子组测序和生物信息学分析在明尼苏达州罗切斯特市的梅奥个体化医学中心进行。结果26例患者中，有8例自然存活，有6例死亡，12例接受了肝移植。在研究纳入后21天，所有被移植的人都还活着。26名患者中有22名表现为ALF。我们发现了与11个基因相关的12个变异体。最常见的变异是SERPINB11基因中的rs4940595，在26例患者中有23例被发现。该变体具有终止密码子。尚无与该变异有关的疾病报道。第二个最常见的变异是CYP2D6基因中的rs1135840。该突变是一种missense_variant，据报道与抗结核治疗的肝毒性有关。我们的患者均未接受这种疗法。我们还发现，在自发存活的患者（75％）与死亡或进行肝移植的患者（分别为30.5％和25％）之间，CYP2D7基因的rs1800754和CYP2D6基因的rs1135840之间存在明显的不对称分布。讨论我们在病因不确定的成年人中发现了11个与ALF显着相关的基因的12个变体。我们还发现自发存活者和死亡或接受肝移植者之间分别属于CYP2D7和CYP2D6基因的2个变异体的明显不对称分布。SERPINB11和CYP2D6基因的两个最常见变体rs4940595和rs1135840 在我们的ALF患者中发现的氟利昂被描述为分别在对抗传染病的出现和与抗结核治疗的肝毒性有关的适应性反应中具有潜在的重要性。我们的研究结果需要扩大，以包括更多具有不确定性ALF以及病毒，药物毒性和自身免疫病因的患者，以确定我们的发现是否与特定病因，不确定性或总体ALF综合征本身有关。