Abstract
BACKGROUND: Frameshift variants in the variable number tandem repeat region of mucin-1 (MUC1) cause autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1) but are challenging to detect. We investigated the prevalence in patients with kidney failure of undetermined aetiology and compared Danish families with ADTKD-MUC1. METHODS: We recruited patients with suspected kidney failure of undetermined aetiology at ≤50 years and excluded those with a clear-cut clinical or histopathological kidney diagnoses or established genetic kidney diseases identified thorough medical record review. MUC1 genotyping was performed by SNaPshot analysis, detecting the most common pathogenic cytosine duplication, followed by bioinformatics pipeline VNtyper analysis of short-read sequencing data. RESULTS: Of 172 recruited patients, 123 underwent SNaPshot analyses, which were abnormal in 5/123 patients (4%). Next, VNtyper genotyping was performed in all patients, including the five with abnormal SNaPshot analysis. VNtyper re-identified the common cytosine duplication in all five patients and revealed novel frameshift variants in two additional patients, while the analyses were normal in the remaining 116 patients. All patients carrying frameshift variants in MUC1 fulfilled ADTKD criteria and had a family history of kidney failure. A considerable inter- and intrafamilial variability of chronic kidney disease stage relative to age was observed in families with ADTKD-MUC1. CONCLUSIONS: ADTKD-MUC1 was identified in 7/123 patients (6%) in a selected cohort of kidney failure of undetermined aetiology ≤50 years, and VNtyper effectively identified all pathogenic MUC1 variants.