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Abstract: PO1334

Genetics Analysis of IgA Nephropathy-Discordant Monozygotic Twins

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Cocchi, Enrico, Columbia University, New York, New York, United States
  • Steers, Nicholas J., Columbia University, New York, New York, United States
  • Appel, Gerald B., Columbia University, New York, New York, United States
  • Rao, Maya K., Columbia University, New York, New York, United States
  • Peruzzi, Licia, Turin University, Turin, Italy
  • Gharavi, Ali G., Columbia University, New York, New York, United States

Group or Team Name

  • Gharavi Lab.
Background

Analysis of monozygotic twins can inform about the genetic and environmental basis of disease. We investigated monozygotic twins phenotypically discordant for IgA nephropathy (IgAN), in order to identify possible postzygotic variants that may provide further insights into IgAN pathogenesis.

Methods

We studied 5 pairs of discordant monozygotic twins, and their family members. Immunological analysis evaluated the in vitro secretion of IgA and Genome Sequencing (GS) was employed to identify germline and somatic variants.

Results

Culture of naïve B-cells and T-follicular like helper cells derived from the IgAN cases yielded 1.74 fold higher IgA production compared to cells from their corresponding healthy twins. Genetic analysis of the samples allowed to call ~4 mln (4,068,187 - 4,103,844) SNPs and ~1 mln (992,798–1,027,413) INDELs for each sample. Of those, ~60,000 (60,739–68,027) SNPs and ~50,000 (45,927–53,052) INDELs were discordant between twin pairs. Slightly lower rate were identified in the technical replicate (57,883 SNPs and 51.415 INDELs). Among discordant variants, only ~1,000 (986–1,147) SNPs and ~500 (401-886) INDELs were in coding regions. Further filtering for GnomAD AF, showed ~50 (43-68) SNPs and ~70 (53-109) INDELs had a minor allele frequency <0.0001, and of those just very few variants (9–22 SNPs and 2–7 INDELs) had potential impact on the gene function. We did not detect discordant variants in the same gene between the twin pairs.

Conclusion

Our analysis identified significant differences in IgA production demonstrating the role of the immune system and genetics in IgAN pathogenesis. Consistent with the literature, GS identified discordant variants between twins pairs, most of which are attributable to background errors in variant calling. Further analysis of twin-specific variants and gene sets may allow the identification of postzygotic variants that may be involved in IgAN pathogenesis.

Affected vs. Unaffected variant differences in one of the IgAN discordant twin pairs under analysis