Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases
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 ADTK...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
20 July 2022
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| In: |
Kidney international
Year: 2022, Volume: 102, Issue: 2, Pages: 405-420 |
| ISSN: | 1523-1755 |
| DOI: | 10.1016/j.kint.2022.04.031 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.kint.2022.04.031 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0085253822003842 
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| Author Notes: | Florian J. Wopperer, Karl X. Knaup, Kira J. Stanzick, Karen Schneider, Tilman Jobst-Schwan, Arif B. Ekici, Steffen Uebe, Andrea Wenzel, Stefan Schliep, Carsten Schürfeld, Randolf Seitz, Wanja Bernhardt, Markus Gödel, Antje Wiesener, Bernt Popp, Klaus J. Stark, Hermann-Josef Gröne, Björn Friedrich, Martin Weiß, Nikolina Basic-Jukic, Mario Schiffer, Bernd Schröppel, Bruno Huettel, Bodo B. Beck, John A. Sayer, Christine Ziegler, Maike Büttner-Herold, Kerstin Amann, Iris M. Heid, André Reis, Francesca Pasutto and Michael S. Wiesener |
| Summary: | 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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| Item Description: | Online verfügbar 26 May 2022, Version des Artikels 20 July 2022 Gesehen am 10.03.2023 |
| Physical Description: | Online Resource |
| ISSN: | 1523-1755 |
| DOI: | 10.1016/j.kint.2022.04.031 |