Department of Pediatrics, University Hospital Cologne and University of Cologne, Faculty of Medicine, Cologne, Germany; Center for Rare Diseases, University Hospital Cologne and Medical Faculty, University of Cologne, Cologne, Germany.
Department of Pediatrics, University Hospital Cologne and University of Cologne, Faculty of Medicine, Cologne, Germany.
Kidney Int. 2021 Sep;100(3):650-659. doi: 10.1016/j.kint.2021.04.019. Epub 2021 Apr 30.
Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.
常染色体隐性多囊肾病 (ARPKD) 是一种严重的儿童期疾病，其临床特征为肾脏和肝脏的纤维囊性改变。ARPKD 的主要病因是编码大跨膜蛋白多囊蛋白的 PKHD1 基因的变异。ARPKD 观察到的临床异质性的潜在机制仍不完全清楚，部分原因是基因型-表型相关性仅限于 PKHD1 中的双等位基因无效变异与最严重表型的关联。在这项观察性研究中，我们分析了来自两个独立队列的 304 名 ARPKD 患者的深度临床数据集，并在儿童和青少年时期确定了新的基因型-表型相关性。双等位基因无效变异通常表现为严重的病程。此外，我们的数据表明，PKHD1 中的受影响区域对于确定表型很重要。受影响的纤维蛋白胱氨酸 709-1837 氨基酸的两个错义变异或该区域的错义变异和较少的无效变异的患者很少发展为慢性肾衰竭，而受影响的纤维蛋白胱氨酸 1838-2624 氨基酸的错义变异的患者则具有更好的肝脏预后。影响纤维蛋白胱氨酸 2625-4074 氨基酸的变异与较差的肝脏预后相关。因此，我们的数据扩展了对儿科 ARPKD 患者基因型-表型相关性的理解，并为更精确和个性化的咨询和治疗方法奠定了基础。
