Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
Hepatology. 2019 Sep;70(3):899-910. doi: 10.1002/hep.30515. Epub 2019 Mar 21.
Biliary atresia (BA) is the most common cause of end-stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations-a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole-exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient-parent trios, from the National Institute of Diabetes and Digestive and Kidney Diseases-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a prespecified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other noncholestatic diseases. Conclusion: WES identified biallelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN data set; the dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome.
胆道闭锁（BA）是儿童终末期肝病的最常见原因，也是小儿肝移植的主要指征，但潜在病因仍不清楚。大约 10%的胆道闭锁患儿存在各种左右侧体缺陷（异位症），包括脾脏异常和复杂的心脏畸形——这是一个独特的亚组，通常被称为胆道闭锁脾畸形（BASM）综合征。我们假设，通过对受影响队列进行全外显子组测序（WES），可以鉴定出将左右特征与 BASM 患者胆道闭锁的病因发病机制联系起来的遗传因素。来自国家糖尿病、消化和肾脏疾病研究所支持的儿童肝脏疾病研究网络（ChiLDReN）的 67 名 BASM 患者的 DNA 标本，包括 58 名患者-父母三亲体，接受了 WES。根据致病性、人群频率和遗传模式，从与纤毛发育不良和/或功能障碍或胆汁淤积相关的 2016 个预先指定基因中衍生出候选基因变体，对其进行优先级排序。5 名 BASM 患者携带多囊肾病 1 样 1（PKD1L1）的罕见且可能具有破坏性的双等位基因变异，该基因与鱼类、小鼠和人类的纤毛钙信号传导和胚胎左右侧确定有关。在另外 3 名受试者中发现了杂合 PKD1L1 变体。对一个 BASM 患者可用的肝脏进行免疫组织化学分析显示，与正常肝脏和受其他非胆汁淤积性疾病影响的肝脏相比，胆管上皮中的 PKD1L1 表达减少。结论：WES 在 ChiLDReN 数据集的 8 名 BASM 患者中鉴定出 PKD1L1 的双等位基因和杂合变体；PKD1L1 在左右确定和纤毛功能中的双重作用表明，PKD1L1 是 BASM 综合征的一个具有生物学意义的、胆管细胞表达的候选基因。
