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Kidney Week

Abstract: SA-PO960

The Genetics of Idiopathic Nephrotic Syndrome at the Population Level

Session Information

Category: Glomerular Diseases

  • 1402 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Wooden, Benjamin, Columbia University, New York, New York, United States
  • Jin, Gina, Columbia University, New York, New York, United States
  • Mitrotti, Adele, Columbia University, New York, New York, United States
  • Gupta, Yask, Columbia University, New York, New York, United States
  • Elliott, Mark, Columbia University, New York, New York, United States
  • Lim, Tze Yin, Columbia University, New York, New York, United States
  • Canetta, Pietro A., Columbia University, New York, New York, United States
  • Marasa, Maddalena, Columbia University, New York, New York, United States
  • Khan, Atlas, Columbia University, New York, New York, United States
  • Montini, Giovanni, IRCCS Policlinico di Milano, Milano, Lombardia, Italy
  • Tasic, Velibor, University Children's Hospital, Skopje, Skopje, Macedonia (the former Yugoslav Republic of)
  • Giordano, Mario, Pediatric Hospital "Giovanni XXIII", Bari, Puglia, Italy
  • Scolari, Francesco, Universita degli Studi di Brescia, Brescia, Lombardia, Italy
  • Conti, Giovanni, Azienda Ospedaliera Universitaria "G. Martino", Messina, Sicily, Italy
  • Magistroni, Riccardo, Universita degli Studi di Modena e Reggio Emilia, Modena, Emilia-Romagna, Italy
  • Bomback, Andrew S., Columbia University, New York, New York, United States
  • Kiryluk, Krzysztof, Columbia University, New York, New York, United States
  • Fiaccadori, Enrico, Istituto Giannina Gaslini, Genova, Liguria, Italy
  • Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Caliskan, Yasar, Saint Louis University, Saint Louis, Missouri, United States
  • D'Agati, Vivette D., Columbia University, New York, New York, United States
  • Ghiggeri, Gian Marco, Istituto Giannina Gaslini, Genova, Liguria, Italy
  • Gharavi, Ali G., Columbia University, New York, New York, United States
  • Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
Background

Genetics play an important role in idiopathic nephrotic syndrome (NS), but our current understanding of clinical-genetic correlations is drawn from small or highly selected studies, with limited representation of different ancestries, ages of onset, and responses to therapy. Here, we present results from a large and broadly-representative cohort of patients with INS who underwent whole exome sequencing.

Methods

2,009 patients were enrolled and sequenced. The cohort included patients with proteinuric kidney disease with a biopsy showing FSGS or minimal change disease, or NS without biopsy. Patients with a known secondary cause were excluded. The cohort included children and adults of different genetic ancestries, irrespective of family history of NS or prior response to immunosuppression.

Results

Overall, 10.6% of patients were found to have a monogenic variant known to be associated with inherited NS. Across genetic ancestries, the rates of monogenic variant discovery were largely similar, with the notable exception being patients of African ancestry, in whom non-APOL1 Mendelian variants were much less common. Overall, the highest rate of discovery was in steroid-resistant pediatric patients. In adult-onset disease, there was also a significant rate of monogenic variant discovery, including in steroid-sensitive patients -- most of this group featured heterozygous COL4A variants. Pathway analysis showed that GBM-related variants were most common in adult-onset cases, while podocyte genes predominated in pediatric disease. APOL1 high-risk genotypes were associated with risk of ESKD within individuals of African ancestry, as well as faster eGFR decline even in steroid sensitive cases.

Conclusion

In this large cohort of patients with idiopathic NS, exome sequencing analyses provide a diagnostic roadmap for clinical-genetic correlations across the lifespan, ancestry, phenotype, and response to immunosuppression.