*Purpose: The prevalence of ESRD in the United States was 2,160.7 cases per one million individuals in 2016, and a primary cause of ESRD was assigned in 84.8% of cases. Primary causes of ESRD were attributed to: Diabetes (45.4%), hypertension (30.3%), glomerulonephritis (18.6%), and cystic kidney disease (5.7%), with ~40% of cases having an identifiable genetic cause. The iGeneTRAiN is a multi-site consortium that encompasses genome-wide genotyping from ~51,210 solid-organ transplant subjects from > 30 genetic studies. We aimed to detect genetic duplications and/or deletions, which may underpin ESRD, using gene copy number variant (CNV) analyses. Of these samples, (n=28,015) 54% (63.3% recipient, 36.7% donor) are from kidney transplant cohorts.

*Methods: Genome-wide genotyping data was obtained using the TxArray (ThermoFisher), comprising ~782,000 genetic variants with tailored content for transplant-specific pathways and prior published associations. CNVs were examined using: (i) the BRLMM-P algorithm and (ii) the recent Axiom Analysis Suite 4.0 (AAS 4.0) and analyzed and visualized on the Integrative Genomics Viewer (IGV) platform. We examined 1,792 a priori CNV regions of interest. For one of these a priori regions, we specifically looked at CNVs in NPHP1, where 2 copy CNV gene deletions cause Nephronophthisis, the most common genetic disorder causing pediatric ESRD.

*Results: CNVs were analyzed to date from 17,128 and 4,354 DNA samples, respectively, on the BRLMM-P and AAS 4.0 platforms. CNVs across the 1,792 regions were observed in 21.4%-58.0% of study participants, with 2 copy gene deletions observed in 0.9% of individuals across all cohorts. The number of CNVs detected correlated to cohort size and ancestral make-up. Twenty-nine homozygous deletions, 52 heterozygous deletions, and 35 duplications of NPHP1 were discovered in combined cohorts of 6,649 kidney transplant recipients using AAS 4.0.

*Conclusions: We can reliably ascertain CNV deletion and duplication states, in regions that are established to cause ESRD, in expected frequencies. Expansion of CNV screening for the 1,792 a priori regions and genome-wide CNV discovery is ongoing across all 51,210 samples in the iGeneTRAiN cohorts. We aim to further characterize and discover genetic contributions of primary end-stage diseases, which could impact patient management/treatment and long-term outcomes.

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