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Abstract: PO1642

Discovery of Genetic Modifiers in Thin Basement Membrane Nephropathy (TBMN) Using Pedigree-Based Whole-Exome Sequencing

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Al-Rabadi, Laith, University of Utah Health, Salt Lake City, Utah, United States
  • Lin, Edwin, University of Utah Health, Salt Lake City, Utah, United States
  • Gorsi, Bushra, University of Utah Health, Salt Lake City, Utah, United States
  • Sauer, Lydia, University of Utah Health, Salt Lake City, Utah, United States
  • Bernstein, Paul, University of Utah Health, Salt Lake City, Utah, United States
  • Pezzolesi, Marcus G., University of Utah Health, Salt Lake City, Utah, United States
  • Gregory, Martin C., University of Utah Health, Salt Lake City, Utah, United States
Background

TBMN is caused by heterozygosity in COL4A3 or COL4A4, and is the carrier state of autosomal recessive Alport syndrome (ARAS). TBMN is less severe than ARAS, but its phenotype can range from asymptomatic microscopic hematuria and/or low-grade proteinuria, focal segmental glomerulosclerosis, to end-stage renal disease (13-25% in patients >60 years). The cause of phenotypic heterogeneity in TBMN is unknown. Previously, we found an autosomal dominant pattern of transmission of isolated microscopic hematuria and low-grade proteinuria in two large pedigrees in Utah with ARAS, which led us to hypothesize that genetic modifiers may affect the severity of TBMN.

Methods

Based on pedigree analysis, 64 participants from two large families with characterized COL4A3 mutation were recruited for WES. In order to identify candidate disease-modifying genes, we used Pedigree-VAAST (pVAAST), a probabilistic algorithm for disease gene prioritization that uses pedigree information to perform linkage analysis. Candidate modifying genes were analyzed using Phevor, an algorithm that performs reprioritization based on information about phenotype, gene function, and disease.

Results

We found 17 candidate modifier genes that co-segregated with hematuria, proteinuria and renal dysfunction (Figure). Of note, GRIP1 co-segregated with the Alport allele, hematuria, proteinuria, renal dysfunction (P=9.4E-04), and had a high biologic correlation score (Phevor score=4.1).

Conclusion

GRIP1 is involved in cell adhesion to extracellular matrix proteins, crucial for kidney morphogenesis, and compound heterozygosity in GRIP1 causes renal agenesis and Fraser syndrome. Whole-exome sequencing in large pedigrees reveal 17 candidate disease-modifying genes in TBMN. Validation studies will be needed to ascertain their role in TBMN.

17 candidate disease-modifying genes in TBMN.
The higher the Phevor score and the lower the p-value, the more likely the candidate gene is a disease-modifying gene.

Funding

  • Private Foundation Support