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Kidney Week

Abstract: TH-PO664

Molecular Genetic Analysis in Patients with Severe Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Obeidova, Lena, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
  • Stekrova, Jitka, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
  • Reiterová, Jana, Department of Nephrology, Charles University and General Teaching Hospital, Prague, Czechia
  • Tesar, Vladimir, Department of Nephrology, Charles University and General Teaching Hospital, Prague, Czechia
Background

Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of chronic kidney disease, frequently diagnosed prenatally. ARPKD is primaly caused by mutations in the PKHD1 gene, nevertheless, phenotype of polycystic kidneys with early onset is present as a part of several syndromes caused by mutations in number of other genes, such as HNF1β, PKD1, PKD2, NPHP etc. Thus, the molecular genetic analysis can be very useful in differential diagnosis of polycystic kidneys in young patients. The results of complex molecular genetic analysis of 42 patients with very early onset PKD are presented.

Methods

The molecular analysis was carried out using next-generation sequencing (NGS) method with capture-based library preparation. The panel of about 80 genes associated with the formation of polycystic kidneys was analyzed. Sequencing data were analyzed with an in-house bioinformatic pipeline designed for detection of single nucleotide variants, small indels and CNV (copy-number variation). Due to the existence of pseudogenes, the PKD1 gene was simultaneously analyzed by NGS with amplicon-based library using long-range PCR. The group of patients comprised 39 young patients with polycystic kidneys (16.6±13.4) and three prenatally diagnosed fetuses. All patients had phenotype compatible with ARPKD, early onset ADPKD or polycystic kidneys in combination with additional abnormities in various organs.

Results

The panel of 80 genes was analyzed in all 42 patients. Thirteen patients harbored mutations in genes PKHD1 or PKD1. In one child combination of one PKHD1 and one TMEM237 mutation was found (p.I2957T and p.A18X, respectively). Such a finding could explain phenotype of polycystic kidneys arising in a young age of this patient. But mutations in other genes were also found in 13 patients: TMEM67, NPHP4, OFD1, BBS1, BBS12, PEX6. These genes with detected mutations are associated with nephronophthisis and developmental abnormalities of kidneys. These heterogeneous findings mirror variable and unclear phenotype of young patients with polycystic kidneys.

Conclusion

Because of an etiologic heterogeneity of polycystic kidney disease phenotype, especially in patients with polycystic kidneys arising prenatally or in a very early age, the complex mutational analysis of several genes is needed for reliable diagnosis.

Supported by the grant projects GAUK 1015 and PROGRES- Q25/LF1

Funding

  • Government Support - Non-U.S.