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Abstract: FR-PO795

Genotype-Phenotype Correlation for the COL4A3 2881+1 G>A Founder Mutation in the Croatian Population

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Ljubanovic, Danica Galesic, University of Zagreb School of Medicine, Clinical Hospital Dubrava, Zagreb, Croatia
  • Horacek, Matija, School of medicine, University of Zagreb, Karlovac, Croatia
  • Nikuseva-Martic, Tamara, School of Medicine, University of Zagreb, Zagreb, Croatia
  • Senjug, Petar, University Hospital Dubrava, Zagreb, Croatia
  • Senjug Perica, Marija, Children's Hospital Srebrnjak, Zagreb, Croatia
  • Oroz, Maja, School of Medicine, University of Zagreb, Zagreb, Croatia
  • Klaric, Dragan, General Hospital Zadar, Zadar, Croatia
  • Saraga, Marijan, University Hospital in Split, Split, Croatia
  • Milosevic, Danko, Zagreb School of Medicine, Clinical Hospital Centre Zagreb, Zagreb, Croatia
  • Galesic, Kresimir, Dubrava University Hospital, Zagreb, Croatia
Background

Alport syndrome (AS) and thin glomerular basement membrane nephropathy (TBMN) are genetically heterogenic disorders caused by mutations in COL4A3, COL4A4 and COL4A5 genes. Genetic heterogeneity with various types and number of mutations with no mutational “hot spots” can make diagnostic process challenging. Some type of mutations increase the likelihood of a severe phenotype but recent studies also showed that same mutations can result in different clinical presentation.

Methods

Total of 26 patients from 10 unrelated families with heterozygous for COL4A3 splice donor 2881+1 G>A mutation detected by next generation sequencing (Illumina MiSeq platform) for COL4A3, COL4A4 and COL4A5 genes mutations was tested as part of a project ''Genotype-Phenotype correlation in Alport’s syndrome and Thin Glomerular Basement Membrane Nephropathy'' founded by the Croatian Science Foundation. There were 11 females and 15 male patients, age range 5-72 years (median 44 years).

Results

According to available clinical data majority of patients (88,5%) presented with haematuria and 72,7% with proteinuria. Decline in kidney function was present in 65% of patients; 40% being mild, 15% severe and 10% suffered from end stage renal disease (2 transplanted patients). Three patients had sensorineural hearing impairment. Kidney biopsy was performed in 50% of cases. On light microscopy focal segmental sclerosis was present in 30% of specimens, whereas, electron microscopy showed TBMN in 40%, TBMN with focal lamellation in 20% and changes suggestive of AS (Figure 1) in 40% of patients.

Conclusion

Here we present genotype-phenotype correlation for COL4A3 2881+1 G>A founder mutation in Croatian population showing clinical and pathohistological heterogeneity. Therefore, identification of modifiers causing such heterogeneity is of grave importance for better understanding of collagen IV nephropathies.

Funding

  • Government Support - Non-U.S.