Abstract: TH-PO449
Small but Clinically Relevant Contribution of Copy Number Variations (CNVs) to Idiopathic Nephrotic Syndrome
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Lim, Tze Yin, Columbia University, New York, New York, United States
- Gupta, Yask, Columbia University, New York, New York, United States
- Ke, Juntao, Columbia University, New York, New York, United States
- Mitrotti, Adele, Columbia University, New York, New York, United States
- Jin, Gina, Columbia University, New York, New York, United States
- Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
- Saleem, Moin, University of Bristol, Bristol, Bristol, United Kingdom
- Gharavi, Ali G., Columbia University, New York, New York, United States
- Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
- Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
Background
Idiopathic Nephrotic Syndrome (INS) is a frequent cause of kidney failure. The utility of genetic diagnostics within the context of rare variants affecting Mendelian NS-associated genes have been demonstrated on patients with various kidney disease. Nevertheless, genetic studies have overwhelmingly assessed the contribution of single nucleotide variants while the contribution of rare Copy Number Variations (CNV) to INS remains poorly understood.
Methods
We conducted chromosomal DNA microarray (CMA) genotyping on a multi-ethnic cohort of 3,600 INS patients across ages of onset and response to immunosuppressive therapy. An interim analysis of 2,230 INS cases was conducted. To extract CNVs, we used PennCNV with default parameters. Predicted CNVs were annotated against the CNV start and stop boundaries of 221 known Genomic Disorders (GD) and a curated list of 126 genes that, when mutated, are known to cause INS/FSGS or a phenocopy of it. A subgroup analysis will be conducted after the removal of solved cases via exome sequencing, partitioning by age of onset, response to therapy, and genetic ancestry.
Results
18 of 2,230 INS individuals (0.8%) carried a GD-CNV without significant enrichment for a particular subcategory. Notably, we identified 6 (0.3%) individuals with smaller deletions that encompassed INS-associated genes for which a loss-of-function mechanism of disease determination is known: NPHS1 (N=2), FRAS1, HNF1B, LMX1B, and WDR73.
Conclusion
This interim analysis showed that the overall CNV diagnostic rate for INS is relatively low, (< 2%), but should not be overlooked since these variants add to the overall genetic diagnostic workup and have direct implications in clinical management for NS (ex steroid avoidance) and risk stratification for extra-urinary complications associated to these variants.
Funding
- NIDDK Support