Department of Molecular Biology and Genetics, Faculty of Science, İhsan Doğramacı Bilkent University, Ankara, Turkey.
Department of Pediatrics, Başkent University Faculty of Medicine, Ankara, Turkey.
J Cell Mol Med. 2024 Jun;28(11):e18485. doi: 10.1111/jcmm.18485.
Genome-wide approaches, such as whole-exome sequencing (WES), are widely used to decipher the genetic mechanisms underlying inter-individual variability in disease susceptibility. We aimed to dissect inborn monogenic determinants of idiopathic liver injury in otherwise healthy children. We thus performed WES for 20 patients presented with paediatric-onset recurrent elevated transaminases (rELT) or acute liver failure (ALF) of unknown aetiology. A stringent variant screening was undertaken on a manually-curated panel of 380 genes predisposing to inherited human diseases with hepatobiliary involvement in the OMIM database. We identified rare nonsynonymous variants in nine genes in six patients (five rELT and one ALF). We next performed a case-level evaluation to assess the causal concordance between the gene mutated and clinical symptoms of the affected patient. A genetic diagnosis was confirmed in four rELT patients (40%), among whom two carried novel mutations in ACOX2 or PYGL, and two had previously-reported morbid variants in ABCB4 or PHKA2. We also detected rare variants with uncertain clinical significance in CDAN1, JAG1, PCK2, SLC27A5 or VPS33B in rELT or ALF patients. In conclusion, implementation of WES improves diagnostic yield and enables precision management in paediatric cases of liver injury with unknown aetiology, in particular recurrent hypertransaminasemia.
全基因组方法，如外显子组测序（WES），被广泛用于破译疾病易感性个体间变异性的遗传机制。我们旨在剖析 otherwise 健康的儿童中特发性肝损伤的先天性单基因决定因素。因此，我们对 20 名表现为小儿发作性复发性转氨酶升高（rELT）或不明病因的急性肝衰竭（ALF）的患者进行了 WES。在 OMIM 数据库中，我们对 380 个具有肝肠受累易感性的遗传性人类疾病的手动编辑基因面板进行了严格的变异筛选。我们在六名患者（五名 rELT 和一名 ALF）的九个基因中发现了罕见的非同义变异。接下来，我们进行了病例水平评估，以评估受影响患者的基因突变与临床症状之间的因果一致性。在四名 rELT 患者（40%）中确认了遗传诊断，其中两名患者携带 ACOX2 或 PYGL 中的新突变，两名患者携带 ABCB4 或 PHKA2 中的先前报道的病态变异。我们还在 rELT 或 ALF 患者中检测到 CDAN1、JAG1、PCK2、SLC27A5 或 VPS33B 中具有不确定临床意义的罕见变异。总之，WES 的实施提高了诊断率，并使病因不明的儿童肝损伤，特别是复发性高转氨酶血症的精准管理成为可能。
