Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; Research Center on Rare Kidney Diseases (RECORD), University Hospital Erlangen, Erlangen, Germany.
Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Kidney Int. 2022 Aug;102(2):405-420. doi: 10.1016/j.kint.2022.04.031. Epub 2022 May 26.
Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation.
常染色体显性遗传性肾小管间质性肾病 (ADTKD) 由至少五个基因中的突变引起，通常导致中年肾衰竭。在整个文献中，已经报道了数量不等的家族，其中无法发现突变，因此被称为未特指的 ADTKD。在这里，我们旨在阐明我们的 ADTKD 登记处中这些疾病的遗传原因。对所有已知的 ADTKD 基因进行测序，然后对 MUC1 的 dupC（七个连续胞嘧啶中的一个额外胞嘧啶）突变进行 SNaPshot 微测序。然后依次分析包含 560 个与肾脏疾病（肾瘤）相关的基因的虚拟面板和外显子测序。验证和测试变体的分离。在登记处的 45 个家族中，发现了已知的 ADTKD 基因的突变，主要是在 MUC1 中。然后可以将 16 个家族称为未特指的 ADTKD，其中 9 个家族在肾瘤中显示出诊断性变体（4 个在 COL4A5 中，2 个在 INF2 中，1 个在 COL4A4、PAX2、SALL1 和 PKD2 中）。在另外 7 个家族中，外显子组测序分析在 ADTKD 的新候选基因中产生了潜在的疾病相关变体；通过数据库分析和全基因组关联研究进行评估。对于我们的 ADTKD 登记处的绝大多数，我们能够达到分子遗传学诊断。然而，确实有一小部分家族受到经典描述为肾小球实体的疾病的影响。因此，不完全的临床表型和非典型的临床表现可能导致 ADTKD 的分类。外显子组测序鉴定的新候选基因需要进一步的功能验证。
