openRxiv

Introduction Autosomal dominant tubulointerstitial kidney disease due to MUC1 variants (ADTKD- MUC1 ) is caused by pathogenic variants leading to a frameshift in the MUC1 gene, most often because of the duplication of a cytosine in a 7-cytosine stretch within the coding variable number tandem repeat (VNTR). It has been regarded as genotypically uniform despite marked clinical heterogeneity. However, as the duplication can arise in any repeat unit, the length of the toxic MUC1-frameshift protein (MUC1-fs) may differ substantially between patients. We thus hypothesised that MUC1-fs length may determine disease severity. Methods In this retrospective cohort study, we evaluated 49 patients with genetically confirmed ADTKD- MUC1 . Mutant VNTR alleles were reconstructed by Oxford Nanopore long-read sequencing. The correlation between total and MUC1-fs length and age at kidney failure (KF) was assessed using statistical models accounting for familial clustering. ResultsMedian KF-free survival was 43 years (95% CI 37–55) for MUC1-fs above the median (>780 amino acids) versus 65 years (95% CI 54–not reached) below it (log-rank p = 0.0039). MUC1-fs length was associated with KF (HR 1.19 per 100 amino acids, 95% CI 1.03–1.37, p = 0.015). The estimate was stable across five handlings of familial clustering, including leave-one-family-out and random one-per-family sampling. Longer MUC1-fs was also correlated with faster eGFR decline. By contrast, the total length of the mutant protein showed a weaker association with KF, and no association when both measures were modelled together, suggesting that the signal lies in the frameshifted portion rather than in overall allele size.Conclusions In this exploratory cohort, MUC1-fs length, determined by the position of the duplication within the VNTR, was associated in a graded manner with age at KF, independently of familial clustering. These findings suggest that ADTKD- MUC1 is not genotypically uniform and that reporting the frameshift position could refine prognosis. Lay Summary ADTKD- MUC1 is an inherited kidney disease. Nearly all patients carry the same mutation, which has supported the view that the disease runs a similar course in everyone. It does not. The mutation falls within a long tract of repeated DNA, and its position along that tract varies between families. That position sets the size of the abnormal protein the kidney cells accumulate: the earlier the mutation, the larger the abnormal protein. Routine genetic tests cannot read this tract reliably, so we used sequencing able to span it from end to end. Across 49 patients from 24 unrelated kindreds, median age at kidney failure was 43 years in the group making the largest abnormal protein and 65 years in the group making the smallest. Determining where the mutation falls therefore adds prognostic information that the standard test cannot give, and larger cohorts should now confirm it.