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Kidney Week

Abstract: PO1350

Prevalence of Autosomal Dominant Tubulointerstitial Kidney Disease in the German Chronic Kidney Disease (GCKD) Cohort

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Popp, Bernt, Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  • Ekici, Arif, Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  • Knaup, Karl Xaver, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
  • Eckardt, Kai-Uwe, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
  • Schiffer, Mario, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
  • Reis, André, Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  • Wiesener, Michael Sean, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
Background

Exome sequencing (ES) studies in chronic kidney disease (CKD) cohorts could identify pathogenic variants in ~10%. This implies underdiagnosis of hereditary CKD. Tubulointerstitial kidney diseases (TKD), showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose. Disorders associated with a tubulointerstitial phenotype include autosomal dominant TKD (ADTKD), mitochondrially inherited TKD (MITKD), nephronophthisis (NPHP) and Collagen4 (COL4) diseases.

Methods

We used a targeted panel (29 genes) and MUC1-SnaPshot to sequence 271 DNAs, selected by clinical criteria from 5,217 individuals in the GCKD (German CKD) cohort.

Results

We identified 33 pathogenic small variants. Of these 27 (81.8%) were in COL4 genes, the largest group being 15 COL4A5 variants with 9 unrelated individuals carrying c.1871G>A, p.(Gly624Asp). We found three typical cysteine variants in UMOD, a novel missense, and a novel splice variant in HNF1B and the homoplastic MTTF variant m.616T>C. Copy-number analysis identified a heterozygous COL4A5 deletion, and a duplication/deletion of HNF1B, respectively. Overall, we found pathogenic variants in 12.5% (34/271 individuals) and variants of unknown significance in 9.6%.
This yield is high despite considering the targeted design and PKD1/2 exclusion. To explain this difference we compared our findings to the largest ES study in adults with CKD by random sampling. None of the 10,000 simulations resulted in an equal or higher yield (p<0.0001). Variant classification differences were excluded using automated ACMG classifiers.

Conclusion

Our study shows that >10% of individuals with certain clinical features carry disease variants in genes associated with TKD. COL4 genes constitute the largest fraction, implying that these are easily overlooked when applying clinical criteria for Alport syndrome. We also identified variants easily missed by some ES pipelines. Bioinformatic predictions paired with gold standard diagnostics for MUC1 (SnaPshot) could not identify the typical cytosine duplication (”c.428dupC”) in any individual of this cohort, implying that ADTKD-MUC1 is rare. Finally, our results indicate that the filtering criteria applied enriched for individuals with an underlying genetic disorder.

Funding

  • Government Support – Non-U.S.