Zhang Jiahui, Zhang Changming, Gao Erzhi, Zhou Qing
Life Sciences Institute, The Key Laboratory of Biosystems Homeostasis & Protection of Ministry of Education, Zhejiang University, Hangzhou, China.
Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
Kidney Dis (Basel). 2021 Sep 29;7(6):425-437. doi: 10.1159/000519095. eCollection 2021 Nov.
At least 10% of adults and most of the children who receive renal replacement therapy have inherited kidney diseases. These disorders substantially decrease their life quality and have a large effect on the health-care system. Multisystem complications, with typical challenges for rare disorders, including variable phenotypes and fragmented clinical and biological data, make genetic diagnosis of inherited kidney disorders difficult. In current clinical practice, genetic diagnosis is important for clinical management, estimating disease development, and applying personal treatment for patients.
Inherited kidney diseases comprise hundreds of different disorders. Here, we have summarized various monogenic kidney disorders. These disorders are caused by mutations in genes coding for a wide range of proteins including receptors, channels/transporters, enzymes, transcription factors, and structural components that might also have a role in extrarenal organs (bone, eyes, brain, skin, ear, etc.). With the development of next-generation sequencing technologies, genetic testing and analysis become more accessible, promoting our understanding of the pathophysiologic mechanisms of inherited kidney diseases. However, challenges exist in interpreting the significance of genetic variants and translating them to guide clinical managements. Alport syndrome is chosen as an example to introduce the practical application of genetic testing and diagnosis on inherited kidney diseases, considering its clinical features, genetic backgrounds, and genetic testing for making a genetic diagnosis.
Recent advances in genomics have highlighted the complexity of Mendelian disorders, which is due to allelic heterogeneity (distinct mutations in the same gene produce distinct phenotypes), locus heterogeneity (mutations in distinct genes result in similar phenotypes), reduced penetrance, variable expressivity, modifier genes, and/or environmental factors. Implementation of precision medicine in clinical nephrology can improve the clinical diagnostic rate and treatment efficiency of kidney diseases, which requires a good understanding of genetics for nephrologists.
接受肾脏替代治疗的成年人中至少10%以及大多数儿童患有遗传性肾脏疾病。这些疾病严重降低了他们的生活质量，并对医疗保健系统产生了重大影响。多系统并发症以及罕见疾病面临的典型挑战，包括可变的表型以及零散的临床和生物学数据，使得遗传性肾脏疾病的基因诊断变得困难。在当前的临床实践中，基因诊断对于临床管理、评估疾病发展以及为患者应用个性化治疗至关重要。
遗传性肾脏疾病包括数百种不同的病症。在此，我们总结了各种单基因肾脏疾病。这些疾病是由编码多种蛋白质的基因突变引起的，这些蛋白质包括受体、通道/转运蛋白、酶、转录因子以及可能在肾外器官（骨骼、眼睛、大脑、皮肤、耳朵等）中也起作用的结构成分。随着下一代测序技术的发展，基因检测和分析变得更加容易获得，促进了我们对遗传性肾脏疾病病理生理机制的理解。然而，在解释基因变异的意义并将其转化以指导临床管理方面仍存在挑战。考虑到Alport综合征的临床特征、遗传背景以及用于基因诊断的基因检测，我们选择以它为例介绍基因检测和诊断在遗传性肾脏疾病中的实际应用。
基因组学的最新进展突出了孟德尔疾病的复杂性，这是由于等位基因异质性（同一基因中的不同突变产生不同的表型）、基因座异质性（不同基因中的突变导致相似的表型）、外显率降低、表达可变、修饰基因和/或环境因素。在临床肾脏病学中实施精准医学可以提高肾脏疾病的临床诊断率和治疗效率，这需要肾脏病学家对遗传学有很好的理解。
