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Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases

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.

Publication metadata

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


DOI: 10.1016/j.kint.2022.04.031

PubMed id: 35643372


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Funder referenceFunder name
387509280–SFB 1350