Autosomal Dominant Tubulointerstitial Kidney Diseases

Background: Autosomal dominant tubulointerstitial kidney diseases (ADTKD) are characterized by chronic interstitial nephritis and mutations in UMOD, MUC1, REN, and HNF1Bgenes have been implicated. Advances in molecular diagnostics have improved the diagnosis of ADTKD. We aimed to characterize the patients evaluated for ADTKD at the Nephrogenetics Clinic of our tertiary care hospital. Methods: Adult patients with chronic kidney disease (CKD) of unknown etiology and findings suggestive of chronic interstitial nephritis were investigated for ADTKD. Genetic study was performed stepwise: 1) Next-Generation Sequencing (NGS) analysis for UMOD, REN, HNF1B and SEC61A1 genes; 2) if negative NGS, search for cytosine insertion in the variable-number tandem repeat sequence in the MUC1 gene; 3) if negative, search for HNF1B deletion. Patients with undefined phenotype were analyzed using broader gene panels for CKD in young patients (173 genes), and those with cystic phenotype with a cystic disease panel (72 genes). Negative results are under review. Results: We studied 37 families (33 with suspected ADTKD; 2 cystic; 2 with undefined phenotype) and confirmed an ATDKD genetic diagnosis in 15 families (40.5%), identifying 38 patients (pts). Genetic study revealed: pathogenic MUC1 variants in 4 families (18 pts); UMOD variants in 4 families (11 pts); heterozygous HNF1B variants in 5 families (7 pts). In one family (5 pts) with initially negative results, further testing included whole exome sequencing (WES), and histochemical investigation of fsMUC1, the latter being positive. Reviewing negative results we found: pathogenic COL4A3 variant in 1 family (2 pts); pathogenic homozygous SDCCAG8 variant in 1 family (2 pts); likely pathogenic PAX2 variant in 1 family (3 pts); likely pathogenic PKD1 variant in 1 family (3 pts). Conclusion: We established a genetic diagnosis of ADTKD in 40.5% of the families studied and confirmed a genetic diagnosis of CKD in 54%. The most prevalent genes implicated were MUC1 and UMOD, similar to other ADTKD cohorts. Re-analysis using larger gene panels, WES, and collaboration with reference laboratories increased our diagnostic yield. Using larger gene panels initially, along with specific methods like snapshot for MUC1, could improve future investigations.