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Abstract: FR-PO695

MIP Assay-Based Targeted Gene Resequencing Identifies 22 Novel and Extremely Rare Variants in Known and Putative New Candidate Genes in Lower Urinary Tract Obstruction

Session Information

  • Pediatric Nephrology - 1
    October 25, 2024 | Location: Exhibit Hall, Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1900 Pediatric Nephrology

Authors

  • Zeilmann, Markus Hartmut, Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
  • Ekici, Arif, Department of Human Genetics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
  • Vidic, Clara, Department of Human Genetics, Rheinische Friedrich-Wilhelms-Universitat Bonn, Erlangen, Germany
  • Krebs, Wolfgang, IT Unit, Nuremberg Institute of Technology, Nuremburg, Germany
  • Zaniew, Marcin, Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland
  • Szmigielska, Agnieszka, Department of Pediatrics and Nephrology, Warsaw Medical University, Warsaw, Poland
  • Miklaszewska, Monika, Department of Pediatric Nephrology and Hypertension,Cracow Medical College of the Jagiellonian University, Cracow, Poland
  • Szczepanska, Maria, Department of Pediatrics, Silesian Medical University, Faculty of Medical Sciences in Zabrze, Zabrze, Poland
  • Taranta-Janusz, Katarzyna, Department of Pediatrics and Nephrology, Medical University of Bialystok, Bialystok, Poland
  • Sikora, Przemyslaw, Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland
  • Zachwieja, Katarzyna, Department of Pediatric Nephrology and Hypertension,Cracow Medical College of the Jagiellonian University, Cracow, Poland
  • Hildebrandt, Friedhelm, Division of Pediatric Nephrology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hilger, Alina, Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany

Group or Team Name

  • CaRE for LUTO.
Background

Lower urinary tract obstruction (LUTO) is the main cause of kidney failure in childhood. In about 60% LUTO occurs as posterior urethral valves (PUV).
To date, little is known about the genetic causes of LUTO. Hence, we aimed to decipher the contribution of the known and previously identified candidate genes to the development of LUTO in our cohort of 500 individuals.

Methods

Therefore, 17 candidate genes were evaluated, using single-molecule molecular inversion probe (MIP) assay. After NextGen sequencing, data was filtered using a stringent algorithm including the quality of the reads, population frequency, and pathogenicity in prediction programs as the CADD-phred score to determine novel and extremely rare variants. The filtered variants were subjected to Sanger sequencing for validation and familial segregation if available.

Results

In total 22 different variants were identified in 20 patients in 11 of the re-sequenced genes (figure 1). Four genes were previously described as possible LUTO disease genes, 4 genes were found to reside in close proximity to regions identified in previous LUTO genome-wide association studies (GWAS) and 3 genes are newly identified candidate genes by our group.
All variants matched the known or assumed inheritance patterns for the respective genes.

Conclusion

We suggest that the identified potentially disease-causing variants provide evidence that the underlying genes may be involved in the development of LUTO. Nevertheless, possibly disease-causing variants could only be identified in just 1,8% of all investigated LUTO individuals showing that LUTO is very heterogeneous. Still, the identification of new candidate genes, followed by warranted functional studies on these genes, will lead to a deeper understanding of the development of LUTO.

Fig. 1