Genomic Disorders in CKD across the Lifespan
Authors: Verbitsky Miguel , Krishnamurthy Sarathbabu , Krithivasan Priya , Hughes Daniel , Khan Atlas , Marasà Maddalena , Vena Natalie , Khosla Pavan , Zhang Junying , Lim Tze Y. , Glessner Joseph T. , Weng Chunhua , Shang Ning , Shen Yufeng , Hripcsak George , Hakonarson Hakon , Ionita-Laza Iuliana , Levy Brynn , Kenny Eimear E. , Loos Ruth J.F. , Kiryluk Krzysztof , Sanna-Cherchi Simone , Crosslin David R. , Furth Susan , Warady Bradley A. , Igo Robert P. , Iyengar Sudha K. , Wong Craig S. , Parsa Afshin , Feldman Harold I. , Gharavi Ali G. 
Published: October 2022

Significance Statement
Pathogenic structural genetic variants, also known as genomic disorders, have been associated with pediatric CKD. This study extends those results across the lifespan, with genomic disorders enriched in both pediatric and adult patients compared with controls. In the Chronic Renal Insufficiency Cohort study, genomic disorders were also associated with lower serum Mg, lower educational performance, and a higher risk of death. A phenome-wide association study confirmed the link between kidney disease and genomic disorders in an unbiased way. Systematic detection of genomic disorders can provide a molecular diagnosis and refine prediction of risk and prognosis.

Background
Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility.

Methods
We examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II (n=248), Chronic Renal Insufficiency Cohort (CRIC) study (n=3375), Columbia University CKD Biobank (CU-CKD; n=1986), and the Family Investigation of Nephropathy and Diabetes (FIND; n=1318) compared with 30,746 controls. We also performed a phenome-wide association analysis (PheWAS) of GDs in the electronic MEdical Records and GEnomics (eMERGE; n=11,146) cohort.

Results
We found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0.65%) GDs in controls (OR, 1.7; 95% CI, 1.3 to 2.2). Among adults with CKD, we found recurrent GDs at the 1q21.1, 16p11.2, 17q12, and 22q11.2 loci. The 17q12 GD (diagnostic of renal cyst and diabetes syndrome) was most frequent, present in 1:252 patients with CKD and diabetes. In the PheWAS, dialysis and neuropsychiatric phenotypes were the top associations with GDs. In CRIC participants, GDs were associated with lower serum magnesium, lower educational achievement, and higher mortality risk.

Conclusion
Undiagnosed GDs are detected both in children and adults with CKD. Identification of GDs in these patients can enable a precise genetic diagnosis, inform prognosis, and help stratify risk in clinical studies. GDs could also provide a molecular explanation for nephropathy and comorbidities, such as poorer neurocognition for a subset of patients.

Podcast
This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_04_03_JASN2022060725.mp3