Abstract: PO1670
Genetic Studies of the Etiology and Complications of Nephrotic Syndrome by Large-Scale Exome Sequencing
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Ahram, Dina, Columbia University Irving Medical Center, New York, New York, United States
- Mitrotti, Adele, Columbia University Irving Medical Center, New York, New York, United States
- Dharmadhikari, Avinash V., Columbia University Irving Medical Center, New York, New York, United States
- Jin, Gina Ying, Columbia University Irving Medical Center, New York, New York, United States
- Kil, Byum hee, Columbia University Irving Medical Center, New York, New York, United States
- Cocchi, Enrico, Department of Public Health and Paedriatric Sciences, University of Torino, Torino, Italy
- Scolari, Francesco, Divisione di Nefrologia, Ospedale di Montichiari,, Brescia, Italy
- Saraga, Marijan, Department of Pediatrics, University Hospital of Split,, Split, Croatia
- Milosevic, Danko, Department of Pediatric Nephrology, Dialysis and Transplantation, University Hospital Center Zagreb,, Zagreb, Croatia
- Zaza, Gianluigi, Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy
- Santoro, Domenico, Division of Nephrology, University of Messina,, Messina, Italy
- Montini, Giovanni, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
- Allegri, Landino, Department of Internal Medicine and Nephrology, University of Parma, Parma, Italy
- Esposito, Pasquale, Department of Nephrology, Dialysis and Transplantation, University of Genoa, Genoa, Italy
- Feriozzi, Sandro, Nephrology and Dialysis, Belcolle Hospital, Viterbo, Italy
- Weng, Patricia L., Pediatci Nephrology, University of California Los Angeles., LA, California, United States
- Gesualdo, Loreto, Department of Medicine,University of Bari Aldo Moro, Bari, Italy
- Aggarwal, Vimla, Columbia University Irving Medical Center, New York, New York, United States
- Appel, Gerald B., Columbia University Irving Medical Center, New York, New York, United States
- Fiaccadori, Enrico, Clinical and Experimental Medicine Dept, University Hospital of Parma, Parma, Italy
- Gharavi, Ali G., Columbia University Irving Medical Center, New York, New York, United States
- Caliskan, Yasar, Saint Louis University School of Medicine, Saint Louis, Missouri, United States
- Ghiggeri, Gian Marco, Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Genova, Italy
- Goldstein, David B., Columbia University Irving Medical Center, New York, New York, United States
- Sanna-Cherchi, Simone, Columbia University Irving Medical Center, New York, New York, United States
Group or Team Name
- Sanna Cherchi Lab
Background
Idiopathic nephrotic syndrome (NS) is a major cause of renal failure. NS and its complications, including venous thrombosis, hypercholesterolemia and cancer display strong genetic predisposition. We hypothesize that the utility of exome sequencing (ES) will optimize precision medicine for clinical management of NS and its risk factors.
Methods
ES was performed in 2007 NS patients with variable onset age and steroid responsiveness. ACMG guidelines for clinical variant interpretation were used to classify monogenic causes and risk predisposition for a) NS in curated gene lists (glomerulopathies, N=127; expanded nephropathies, N=679); b) Incidental variants in 59 ACMG actionable-genes; c) Genetic risk for NS complications (Coagulation, N=100; lipid metabolism/cardiovascular risk, N=35); d) Germline cancer predisposition (N=77).
Results
We identified a monogenic cause for NS in 13% of cases, with COL4A3 (2.2%), COL4A5 (1.8%) and WT1 (1.3%) representing the lead causes. Monogenic causes were enriched in FSGS and steroid resistant nephrotic syndrome cases. Analysis of the expanded nephropathy gene panel revealed an additional diagnostic rate of ~1%, representing coincidental diagnoses or phenocopies. APOL1 associated FSGS risk genotypes were identified in 5% of cases. Variants of actionable potential were noted in 2.9% of patients, led by BRCA2 (3.9%), MYBPC3 (3.5%) and LDLR (0.25%). Variants predisposing to coagulation defects, lipid metabolism and cancer risk were found in ~11% of cases. Overall, we identified a monogenic cause or predisposing risk factor to NS or its complications in 27%, corresponding to 1 per 4 cases.
Conclusion
Our results reveal the importance of ES in the diagnosis of NS and its complications, with implications in risk stratification and clinical management. We showed that one every 4 cases carried a genetic variant that has potential to help clinicians optimize precision medicine approaches at the single-patient level. Our results enable designing cost-effective panels to maximize yield in routine clinical practice.
Funding
- Other U.S. Government Support