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Kidney Week

Abstract: SA-PO565

Familial IgA Glomerulonephritis Is Commonly Caused by Pathogenic Variants Associated With Other Genetic Kidney Diseases

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Harraka, Philip Adam, The University of Melbourne Department of Medicine, Northern Health, Melbourne, Victoria, Australia
  • Mahmood, Khalid, Melbourne Bioinformatics, Melbourne, Victoria, Australia
  • Mack, Heather G., The University of Melbourne Department of Surgery in Ophthalmology, East Melbourne, Victoria, Australia
  • Barit, David, The University of Melbourne Department of Medicine, Northern Health, Melbourne, Victoria, Australia
  • Langsford, David, The University of Melbourne Department of Medicine, Northern Health, Melbourne, Victoria, Australia
  • Pianta, Timothy J., Department of Medical Education, University of Melbourne, Melbourne, Victoria, Australia
  • Colville, Deb J., The University of Melbourne Department of Medicine, Northern Health, Melbourne, Victoria, Australia
  • Savige, Judith A., The University of Melbourne Department of Medicine, Northern Health, Melbourne, Victoria, Australia
Background

Genetic studies of families with IgA glomerulonephritis have implicated pathogenic variants in COL4A3-5 and SPRY2 but in few other genes. We have recently identified retinal drusen in IgA glomerulonephritis which is further evidence for complement activation. This study investigated familial IgA disease for pathogenic variants in five candidate gene lists including those reported in IgA nephropathy (102 genes), the complement system (56), drusen in macular degeneration (46), Alport syndrome (3) and FSGS (47).

Methods

Eight unrelated individuals with familial IgA nephropathy were recruited. Family members were examined for haematuria, proteinuria and eGFR. IgA nephropathy was biopsy-proven in the index case and some relatives. Whole exome sequencing of available members in each family was performed and variants curated using the GATK Best Practices pipeline. Variants were examined for a CADD score ≥10 and a minor allele frequency <0.05 in gnomAD, and pathogenic assessments made according to the ACMG criteria. Assessments included pathogenic features in in-silico prediction algorithms (≥2 of PolyPhen-2, SIFT, MutationTaster) and conservation of the affected residue in vertebrates (UCSC Genomics Institute).

Results

Damaging variants were identified in four families (50%) consistent with Alport syndrome in two (COL4A3, COL4A5), Renal Cysts And Diabetes syndrome (HNF1B) in one and C9 deficiency (C9) in one. The COL4A3 variant (p.Gly395Glu) was Likely pathogenic (PP5, PM1, PM2, PP2, PP3) and previously associated with AD Alport syndrome and haematuria. The COL4A5 variant (p.Gly624Asp) is a common hypomorphic variant (PP5, PM1, PM5, PP2, PP3) causing late onset X-linked Alport syndrome. The HNF1B variant (p.Pro437Leu) is Likely Pathogenic (PM2, PP2, PP3, PP5) and previously reported in Renal Cysts And Diabetes syndrome. The C9 (p.Cys54Ter) variant is a Pathogenic nonsense change (PVS1, PP5, PM2, PP3) in a drusen-risk gene associated with a partial C9 complement deficiency.

Conclusion

Half the families with IgA nephropathy examined here had another explanation for their genetic kidney disease. Since IgA deposits occur in up to 20% of normal individuals, apparent familial IgA nephropathy may be secondary to another, concurrent, genetic kidney disease.