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Clinical and Genetic Spectra of Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations in UMOD and MUC1

Olinger, E; Hofmann, P; Kidd, K; Dufour, I; Belge, H; Schaeffer, C; Kipp, A; ... Devuyst, O; + view all (2020) Clinical and Genetic Spectra of Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations in UMOD and MUC1. Kidney International 10.1016/j.kint.2020.04.038. (In press). Green open access

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Abstract

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized. cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. To expand on this, we analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.

Type: Article
Title: Clinical and Genetic Spectra of Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations in UMOD and MUC1
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.kint.2020.04.038
Publisher version: https://doi.org/10.1016/j.kint.2020.04.038
Language: English
Additional information: © 2020 Published by Elsevier Inc., on behalf of the International Society of Nephrology, under a Creative Commons license (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Diagnostic score, Dominant kidney disease, Gout, Mucin-1, Uromodulin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10099660
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