ERA Conference 2026
Online Tool
Facilitates the Diagnosis of ADTKD-MUC1
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is considered the third most common hereditary kidney disease. The ADTKD-MUC1 subtype, in particular, has long posed a diagnostic challenge. The development of VNtyper about three years ago marked a significant advance; however, the tool was not freely available until now and was time-consuming and cumbersome to use. As Jan Halbritter, Freiburg/Germany, explained at the European Renal Association (ERA) conference in Glasgow, the newly developed follow-up online tool “VNtyper 2” enables the rapid identification of pathogenic MUC1 variants using routine sequencing data and, at the same time, makes this specialized diagnostic tool widely accessible in clinical practice.
Among the genes associated with ADTKD, mutations in MUC1 and UMOD account for the majority of cases. Due to previous difficulties in diagnosing MUC1, many affected patients went undiagnosed despite extensive clinical examinations.
Pathophysiology and Genetics
As Jan Halbritter explained, the pathogenic variants in the MUC1 gene are toxic gain-of-function mutations. Approximately 94% of affected patients have a cytosine insertion. MUC1 is primarily expressed in the distal tubule and collecting duct of the kidney. The normal protein is a transmembrane molecule with a large extracellular domain that helps stabilize epithelial cells and maintain their function. ADTKD-MUC1 is caused by frameshift mutations that introduce a premature stop codon. As a result, a misfolded, truncated protein is produced that lacks the normal transmembrane structure. The abnormal protein accumulates within the cell and triggers stress in the endoplasmic reticulum. This leads to cellular dysfunction and progressive tubulointerstitial fibrosis. [1]
Nonspecific clinical presentation
Halbritter emphasized that one of the greatest clinical challenges with ADTKD-MUC1 is its nonspecific presentation. “Patients develop chronic kidney disease (CKD), but without the characteristic features that often indicate hereditary nephropathies: Hematuria is generally absent, proteinuria is minimal or absent entirely, and there are hardly any extrarenal manifestations. Imaging of the kidneys is also nonspecific.” Kidney cysts may occur, but they differ significantly from the cysts typical of ADPKD. [1] “ADTKD-MUC1 can therefore only be diagnosed through genetic testing,” emphasized the expert in nephrogenetics.
Diagnostic Breakthrough with VNtyper
The causative mutations occur in a highly repetitive genomic region known as a Variable Number Tandem Repeat (VNTR). Conventional next-generation sequencing (NGS) technologies rely on short DNA sequence fragments, which are difficult to map accurately within repetitive sequences. As a result, pathogenic MUC1 variants were often not detected in routine genetic testing. “MUC1 therefore represented a diagnostic blind spot for conventional NGS methods,” said Halbritter. Diagnosis required specialized and resource-intensive techniques such as snapshot PCR or long-read sequencing—methods available to only a few laboratories worldwide.
A major breakthrough came in 2023 with the development of VNtyper, a bioinformatics tool that can detect MUC1 frameshift variants from conventional short-read sequencing data. The tool can analyze existing exome datasets and identify disease-causing variants within the VNTR region. In clinical studies, it demonstrated a sensitivity of nearly 97% and a specificity of 100% in selected cohorts. [2] Of particular significance was a retrospective analysis of large cohorts with chronic kidney disease (CKD), in which previously undetected MUC1-positive patients were identified using VNtyper—a clear indication that the disease is significantly more common than previously assumed. [3]
VNtyper 2 paves the way for routine MUC1 diagnostics
Initially, one problem was that using the software required extensive bioinformatics expertise and involved long processing times. This posed a barrier to its widespread adoption in routine clinical diagnostics. To make MUC1 diagnostics more accessible, the European ADTKD Consortium has therefore developed an updated version, VNtyper 2, as reported by Halbritter. The software is available via an online interface and allows users to upload standard genomic data files (BAM files) for automated analysis. The system provides confidence scores that aid in interpreting the results and indicate whether confirmatory testing is necessary.
In the validation studies presented by Halbritter, VNtyper 2 proved to be highly effective for both typical and atypical MUC1 variants. Agreement with established reference methods, such as long-read sequencing, was approximately 94%, while sensitivity remained high provided there was sufficient sequencing coverage. [4]
VNtyper 2 was subsequently applied to more than 3,500 clinical exomes from the Czech Republic, France, Germany, and Ireland. In these unselected cohorts with CKD, ADTKD-MUC1 accounted for approximately 1–2% of cases. [4] This finding suggests that many patients currently classified as cases of unexplained CKD (CKDx) [5] may be suffering from an undiagnosed MUC1-associated disorder. Halbritter emphasized that VNtyper 2 has “democratized” MUC1 diagnostics by making the test accessible to laboratories worldwide.
For example, the online version of VNtyper 2 was made available free of charge to human geneticists (https://vntyper.org). “This is the first step toward treatment: the early diagnosis and identification of these patients.”
Further Challenges in ADTKD
Despite these advances, important scientific questions regarding ADTKD remain unanswered. One of the most striking features is the variability in disease severity, even among relatives who carry the same mutation, said Halbritter. In some families, one person may develop kidney failure as early as young adulthood, while the kidney function of other relatives with the same mutation remains stable well into late adulthood. “We observe this enormous variability and do not yet have a prognostic biomarker,” said Halbritter. Current research within the European ADTKD Consortium is therefore focused on identifying genetic modifiers and environmental factors that could explain this variability. Another hypothesis currently being investigated explores whether the exact structure and length of the abnormal, truncated protein influence pathogenicity and disease progression.
Conclusion: Broadly Implement ADTKD-MUC1 Screening in Clinical Practice possible
- The introduction of VNtyper has significantly advanced the diagnosis of ADTKD-MUC1.
- With VNtyper 2, it is now possible for the first time to offer MUC1 screening as a routine component of clinical exome analyses.
- Wider adoption could significantly increase the number of diagnoses in patients with unexplained familial chronic kidney disease.
- Nephrologists should actively collaborate with their local genetic laboratories to ensure that MUC1 analysis is integrated into standard testing protocols. Otherwise, affected patients could continue to be overlooked despite comprehensive genetic testing.
Further information:
Diagnosis of ADTKD-MUC1-Diagnostik: What can VNtyper 2.0 do?
Source: Unmasking ADTKD-MUC1: clinical presentation and diagnosis challenges; ERA conference 2026, Glasgow, 4. Juni 2926
Literature
[1] Olinger E, et al. Kidney Int. 2020;98(3):717-31
[2] Saei H, et al. iScience. 2023;26(7):107171
[3] Bensouna I, et al. J Am Soc Nephrol. 2025;36(2):256-63
[4] Popp B, et al. medRxiv [Preprint]. 2026. doi: https://doi.org/10.64898/2026.05.27.26352937
[5] Halbritter J, et al. Nephrol Dial Transplant. 2025;40(12):2390-400