Division of Nephrology, University Health Network and University of Toronto, Toronto, ON, Canada.
Nephrol Dial Transplant. 2019 Sep 1;34(9):1453-1460. doi: 10.1093/ndt/gfy261.
Autosomal dominant polycystic kidney disease (ADPKD) is caused primarily by mutations of two genes, PKD1 and PKD2. In the presence of a positive family history of ADPKD, genetic testing is currently seldom indicated as the diagnosis is mostly based on imaging studies using well-established criteria. Moreover, PKD1 mutation screening is technically challenging due to its large size, complexity (i.e. presence of six pseudogenes with high levels of DNA sequence similarity) and extensive allelic heterogeneity. Despite these limitations, recent studies have delineated a strong genotype-phenotype correlation in ADPKD and begun to unravel the role of genetics underlying cases with atypical phenotypes. Furthermore, adaptation of next-generation sequencing (NGS) to clinical PKD genetic testing will provide a high-throughput, accurate and comprehensive screen of multiple cystic disease and modifier genes at a reduced cost. In this review, we discuss the evolving indications of genetic testing in ADPKD and how NGS-based screening promises to yield clinically important prognostic information for both typical as well as unusual genetic (e.g. allelic or genic interactions, somatic mosaicism, cystic kidney disease modifiers) cases to advance personalized medicine in the era of novel therapeutics for ADPKD.
常染色体显性多囊肾病（ADPKD）主要由 PKD1 和 PKD2 两个基因的突变引起。在 ADPKD 阳性家族史的情况下，由于诊断主要基于使用既定标准的影像学研究，因此目前很少进行基因检测。此外，由于 PKD1 突变筛查具有较大的尺寸、复杂性（即存在 6 个具有高度 DNA 序列相似性的假基因）和广泛的等位基因异质性，因此技术上具有挑战性。尽管存在这些局限性，但最近的研究在 ADPKD 中描绘了强烈的基因型-表型相关性，并开始揭示具有非典型表型的病例的遗传基础。此外，将下一代测序（NGS）应用于临床 PKD 基因检测将以降低的成本提供对多种囊性疾病和修饰基因的高通量、准确和全面筛查。在这篇综述中，我们讨论了基因检测在 ADPKD 中的不断发展的适应症，以及基于 NGS 的筛查如何有望为典型和非典型（例如等位基因或基因相互作用、体细胞镶嵌、囊性肾病修饰基因）遗传病例提供临床重要的预后信息，以推进 ADPKD 新型治疗时代的个体化医学。
