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Abstract: SA-PO632

Undiagnosed Genomic Disorders in Adult with CKD

Session Information

Category: Genetic Diseases of the Kidney

  • 803 Genetic Epidemiology and Other Genetic Studies of Common Kidney Diseases

Authors

  • Verbitsky, Miguel, Columbia University, New York, New York, United States
  • Krithivasan, Priya, 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
  • Li, Yifu, Columbia University, New York, New York, United States
  • Yang, Wei, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
  • Kiryluk, Krzysztof, Columbia University, New York, New York, United States
  • Feldman, Harold I., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Gharavi, Ali G., Columbia University, New York, New York, United States
Background

Genomic Disorders (GDs) are caused by pathogenic deletions or duplications of large genomic regions of the genome. GDs are associated with many multiorgan developmental disorders and are enriched in children with chronic kidney disease (CKD), associating with poorer neurocognitive scores.

Methods

We studied the prevalence of GDs in adults with all-cause CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC, N= 3,375) and in the Columbia University CKD cohort (CU-CKD, N= 1,146) and compared them to 21,498 population controls. All samples were genotyped on Illumina microarrays and screened for deletions and duplications that are diagnostic of 131 known GDs.

Results

We detected GDs in 58/4,521 (1.3%) renal patients compared to 134/21,498 (0.6%) population controls (OR = 2.1, p = 1.3 x 10-5). Known GDs in the CKD cohorts included 1q21.1 and 4p16.3 deletions and the 15q13.3, 16p13.11, 17p12, 17q12, 22q11.2 deletions/duplications. These GDs were all undiagnosed in the CU-CKD cohort, while diagnosis data were not available in CRIC. Analysis of available baseline clinical data in CRIC participants demonstrated that GDs are associated with significantly lower serum Mg (p = 7x10-4) and lower educational achievement (p = 8x10-3). We also detected known phenotypic associations for specific syndromes. For example, the 17q12 deletion/duplication syndrome (renal cyst and diabetes syndrome) was detected in 9 CRIC participants and was associated with diabetes (8/9 carriers) and insulin therapy (7/9 carriers) despite normal BMI, as well as hypomagnesemia (7/9 carriers).

Conclusion

GDs are undiagnosed and significantly enriched in adults with CKD, providing a molecular explanation for poorer neurocognition and specific metabolic defects in mutation carriers. Systematic detection of GDs can enable a precise genetic diagnosis and reconcile seemingly disparate clinical findings in patients. Risk stratification with GDs can also remove confounders in ongoing clinical studies, offering an opportunity to better explore causal relationships between CKD and outcomes.

Funding

  • NIDDK Support