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Lookup NU author(s): Florian Wopperer, Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2022 International Society of Nephrology. 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.
Author(s): Wopperer FJ, Knaup KX, Stanzick KJ, Schneider K, Jobst-Schwan T, Ekici AB, Uebe S, Wenzel A, Schliep S, Schurfeld C, Seitz R, Bernhardt W, Godel M, Wiesener A, Popp B, Stark KJ, Grone H-J, Friedrich B, Weiss M, Basic-Jukic N, Schiffer M, Schroppel B, Huettel B, Beck BB, Sayer JA, Ziegler C, Buttner-Herold M, Amann K, Heid IM, Reis A, Pasutto F, Wiesener MS
Publication type: Article
Publication status: Published
Journal: Kidney International
Year: 2022
Volume: 102
Issue: 2
Pages: 405-420
Print publication date: 01/08/2022
Online publication date: 26/05/2022
Acceptance date: 08/04/2022
Date deposited: 21/07/2022
ISSN (print): 0085-2538
ISSN (electronic): 1523-1755
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.kint.2022.04.031
DOI: 10.1016/j.kint.2022.04.031
PubMed id: 35643372
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