Institute of Liver Studies, King's College Hospital, London, United Kingdom; Institute of Liver Studies, King's College London, London, United Kingdom; Pediatric Liver, GI and Nutrition Center and MowatLabs, King's College Hospital, London, United Kingdom.
Institute of Liver Studies, King's College London, London, United Kingdom.
J Pediatr. 2021 Sep;236:124-130. doi: 10.1016/j.jpeds.2021.05.041. Epub 2021 May 21.
To use next generation sequencing (NGS) technology to identify undiagnosed, monogenic diseases in a cohort of children who suffered from acute liver failure (ALF) without an identifiable etiology.
We identified 148 under 10 years of age admitted to King's College Hospital, London, with ALF of indeterminate etiology between 2000 and 2018. A custom NGS panel of 64 candidate genes known to cause ALF and/or metabolic liver disease was constructed. Targeted sequencing was carried out on 41 children in whom DNA samples were available. Trio exome sequencing was performed on 4 children admitted during 2019. A comparison of the clinical characteristics of those identified with biallelic variants against those without biallelic variants was then made.
Homozygous and compound heterozygous variants were identified in 8 out of 41 children (20%) and 4 out of 4 children (100%) in whom targeted and exome sequencing were carried out, respectively. The genes involved were NBAS (3 children); DLD (2 children); and CPT1A, FAH, LARS1, MPV17, NPC1, POLG, SUCLG1, and TWINK (1 each). The 12 children who were identified with biallelic variants were younger at presentation and more likely to die in comparison with those who did not: median age at presentation of 3 months and 30 months and survival rate 75% and 97%, respectively.
NGS was successful in identifying several specific etiologies of ALF. Variants in NBAS and mitochondrial DNA maintenance genes were the most common findings. In the future, a rapid sequencing NGS workflow could help in reaching a timely diagnosis and facilitate clinical decision making in children with ALF.
利用下一代测序（NGS）技术鉴定不明原因单基因疾病的儿童队列患有急性肝衰竭（ALF），病因不明。
我们鉴定了 2000 年至 2018 年间在伦敦国王学院医院因不明病因性急性肝衰竭而住院的 148 名年龄在 10 岁以下的儿童。构建了一个包含 64 个已知可导致 ALF 和/或代谢性肝病的候选基因的定制 NGS 面板。对 41 名可获得 DNA 样本的儿童进行了靶向测序。对 2019 年入院的 4 名儿童进行了外显子组测序。然后比较了鉴定出的具有双等位基因突变的患儿与无双等位基因突变的患儿的临床特征。
在 41 名接受靶向和外显子组测序的儿童中，分别有 8 名（20%）和 4 名（100%）儿童发现纯合子和复合杂合子变异。涉及的基因有 NBAS（3 名儿童）；DLD（2 名儿童）；CPT1A、FAH、LARS1、MPV17、NPC1、POLG、SUCLG1 和 TWINK（各 1 名儿童）。与未发现双等位基因突变的患儿相比，12 名发现双等位基因突变的患儿在发病时年龄更小，死亡率更高：中位发病年龄分别为 3 个月和 30 个月，存活率分别为 75%和 97%。
NGS 成功鉴定了 ALF 的几种特定病因。NBAS 和线粒体 DNA 维持基因的变异最为常见。在未来，快速测序 NGS 工作流程可以帮助及时诊断，并为 ALF 患儿的临床决策提供便利。
