Abstract: FR-OR032

Rare Exonic Variants in Idiopathic Nephrotic Syndrome

Session Information

Category: Genetic Diseases of the Kidney

  • 802 Non-Cystic Mendelian Diseases

Authors

  • Mitrotti, Adele, Columbia University Medical Center, New York, New York, United States
  • Bodria, Monica, G. Gaslini Children Hospital, Genoa, Italy
  • Pontrelli, Paola, University of Bari, Altamura, Bari, Italy
  • Gigante, Maddalena, University of Foggia, Foggia, Italy
  • D'Agati, Vivette D., Columbia University Medical Center, New York, New York, United States
  • Bomback, Andrew S., Columbia University Medical Center, New York, New York, United States
  • Appel, Gerald B., Columbia University Medical Center, New York, New York, United States
  • Gesualdo, Loreto, University of Bari, Altamura, Bari, Italy
  • Pisani, Isabella, University of Parma, Bozzolo (Mantova), Italy
  • Scolari, Francesco, University of Brescia, Montichiari (Brescia), Italy
  • Ghiggeri, Gian Marco, G. Gaslini Children Hospital, Genoa, Italy
  • Krithivasan, Priya, Columbia University Medical Center, New York, New York, United States
  • Gharavi, Ali G., Columbia University Medical Center, New York, New York, United States
  • Goldstein, David B., Columbia University Medical Center, New York, New York, United States
  • Sanna-Cherchi, Simone, Columbia University Medical Center, New York, New York, United States
  • Groopman, Emily, Columbia University Medical Center, New York, New York, United States
  • Fasel, David, Columbia University Medical Center, New York, New York, United States
  • Westland, Rik, Columbia University Medical Center, New York, New York, United States
  • Milo Rasouly, Hila, Columbia University Medical Center, New York, New York, United States
  • Marasa, Maddalena, Columbia University Medical Center, New York, New York, United States
  • Zhang, Junying, Columbia University Medical Center, New York, New York, United States
  • Li, Yifu, Columbia University Medical Center, New York, New York, United States
Background

Idiopathic nephrotic syndrome (NS) is a major cause of end stage renal disease and the molecular diagnosis in the majority of drug-resistant and hereditary forms remains unknown.

Methods

We performed whole exome sequencing in 310 patients with idiopathic NS from 259 independent families. 116 (44%) of these cases were familial and 143 (56%) were sporadic. A case-control exome-wide collapsing analysis for rare functional variants (i.e. burden tests) was performed, comparing 259 index affected by familial or sporadic idiopathic NS with 6,905 controls.

Results

We identified diagnostic or likely pathogenic mutations in 28 cases (10.8%; 15.5% of familial 7.0% of sporadic NS): these included variants in INF2, WT1, LMX1B, and TRPC6. To identify novel susceptibility genes for NS we conducted a rare variant collapsing analysis comparing 259 cases and 6,905 controls. The analysis yielded 25 genes at a p-value <2.5x10-3 with minimal genomic inflation. Among these top-ranking signals, we identified 6 genes implicated in Mendelian forms of NS or structural kidney disease: TRPC6 (rank 3; p=2.01x10-4; OR 12.1); COL4A3 (rank 7; p=5.39x10-4; OR 6.98); UMOD (rank 17; p=1.53x10-3; OR 19.9); ACE (rank 18; p=1.53x10-3; OR 7.0); LMX1B (rank 19; p=1.53x10-3; OR 19.9); and WT1 (rank 24; p=2.39x10-3; OR 15.9). Aggregate analysis of 12 known genes involved in adult-onset NS identified qualifying variants in 30 (11.6%) cases and 152 (2.2%) controls (OR 5.8, p=1.6x10-12). The estimated fraction of disease explained by variants at these genes was 9.4%, similar to that explained by variants identified by prioritization, expert inspection, and segregation tests.

Conclusion

Rare variants collapsing analysis represent a powerful approach to identify known and novel monogenic forms of NS in absence of large pedigrees or segregation data, and holds promises to help dissecting the complex genetic architecture of NS.

Funding

  • Other U.S. Government Support