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Abstract: PO1332

Genomic Disorders Are Associated with CKD Across the Life Span

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Verbitsky, Miguel, Columbia University, New York, New York, United States
  • Krishna Murthy, Sarath Babu, Columbia University, New York, New York, United States
  • Marasa, Maddalena, Columbia University, New York, New York, United States
  • Zhang, Junying, Columbia University, New York, New York, United States
  • Khan, Atlas, Columbia University, New York, New York, United States
  • Wong, Craig S., University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
  • Warady, Bradley A., University of Missouri Kansas City, Kansas City, Missouri, United States
  • Furth, Susan L., The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Crosslin, David R., University of Washington, Seattle, Washington, United States
  • Igo, Robert P., Case Western Reserve University, Cleveland, Ohio, United States
  • Iyengar, Sudha K., Case Western Reserve University, Cleveland, Ohio, United States
  • Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
  • Kiryluk, Krzysztof, Columbia University, New York, New York, United States
  • Parsa, Afshin, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Feldman, Harold I., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Gharavi, Ali G., Columbia University, New York, New York, United States
Background

Genomic Disorders (GDs), caused by pathogenic deletions and duplications (copy number variants, CNV) of large genomic regions of the genome, are a major source of genetic susceptibility for multiple developmental traits and are enriched in pediatric chronic kidney disease (CKD) patients. In the Chronic Kidney Disease in Children Study (CKiD) cohort 1, 4.5% participants carried a GD.

Methods

We extended our previous study in CKiD to cohort 2 and also examined the prevalence of GDs in adults with all-cause CKD enrolled in the Chronic Renal Insufficiency (CRIC, N = 3375), Columbia University CKD (CU-CKD, N=1146) and Family Investigation of Nephropathy and Diabetes (FIND, N=1318) cohorts, comparing them to 30746 controls. CNV calls were based on SNP microarrays and whole exome sequencing and annotated for known GDs. We also performed a phenome-wide association analysis of GDs in the Electronic Medical Records and Genomics (eMERGE, N=11971) cohort.

Results

We found 9/248 (3.6%) CKiD 2 pediatric participants with mild CKD carried a GD, replicating prior findings in pediatric CKD. We next identified GDs in 74/6,679 (1.1%) adult CKD patients in the CRIC, CU-CKD and FIND cohorts, compared to 165/30,746 (0.5%) GDs in controls (OR=1.6, p=5x10-4). Recurrent known GDs in adult CKD patients comprised pathogenic CNVs in 1q21.1, 16p11.2, 17q12 and 22q11.2 loci. The 17q12 GD (renal cyst and diabetes syndrome) was most frequent, detected in 1:252 CKD cases with diabetes. In the phenome-wide analysis of the eMERGE cohort, dialysis was in the top three phenotypic associations with GD carrier status (p<10-3), replicating the case-control association results. Other phenotypic associations for GDs in CRIC participants included lower serum Mg (p=2x10-3) and lower educational achievement (p=8x10-4).

Conclusion

GDs are significantly enriched in children and adults with CKD. Undiagnosed GDs can provide a molecular explanation for renal disease in both adults and children and represent hidden genetic links between CKD and other traits such as poorer neurocognitive performance. Systematic detection of GDs can enable a precise genetic diagnosis and inform prognosis and treatment.

Funding

  • NIDDK Support