4.7 Article

Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases

Journal

KIDNEY INTERNATIONAL
Volume 102, Issue 2, Pages 405-420

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2022.04.031

Keywords

ADTKD; Alport syndrome; exome; MITKD; MUC1; UMOD

Funding

  1. Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nurnberg MD-Thesis Scholarship Program)
  2. Deutsche Forschungsgemeinschaft (German Research Foundation) [387509280-SFB 1350]
  3. Else Kroner-Fresenius-Stiftung
  4. Eva Luise und Horst Kohler Stiftung-Project [2019_KollegSE.04]
  5. Interdisciplinary Center for Clinical Research Erlangen [J70]
  6. Deutsche Forschungsgemeinschaft [PO2366/2-1]

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In our ADTKD registry, a molecular genetic diagnosis was obtained for the majority of families, and novel candidate genes were identified through exome sequencing.
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.

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