Division of Nephrology, Department of Medicine, Columbia University, New York, New York.
Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.
J Am Soc Nephrol. 2023 Apr 1;34(4):607-618. doi: 10.1681/ASN.2022060725. Epub 2022 Oct 27.
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.
Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility.
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.
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.
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.
致病性结构遗传变异，也称为基因组疾病，与儿科 CKD 相关。本研究将这些结果扩展到整个生命周期，与对照组相比，基因组疾病在儿科和成年患者中更为丰富。在慢性肾功能不全队列研究中，基因组疾病也与血清 Mg 降低、教育成绩降低和死亡风险增加有关。表型全基因组关联研究以一种无偏倚的方式证实了肾脏疾病与基因组疾病之间的联系。系统检测基因组疾病可以提供分子诊断，并完善风险和预后预测。
基因组疾病（GDs）与许多合并症结局相关，包括 CKD。鉴定 GDs 具有诊断价值。
我们检查了慢性肾脏病儿童（CKiD）队列 II（n=248）、慢性肾功能不全队列（CRIC）研究（n=3375）、哥伦比亚大学 CKD 生物库（CU-CKD；n=1986）和家族肾病和糖尿病研究（FIND；n=1318）参与者中 GDs 的患病率与 30746 名对照者相比。我们还在电子医疗记录和基因组学（eMERGE；n=11146）队列中进行了 GDs 的表型全基因组关联分析（PheWAS）。
我们在 248 名 CKiD II 参与者中发现了 9 名（3.6%）携带 GD，这复制了儿科 CKD 中的先前发现。我们还在 CRIC、CU-CKD 和 FIND 队列中 6679 名成年 CKD 患者中发现了 GDs，而在 30746 名对照者中发现了 199 名（0.65%）GDs（OR，1.7；95%CI，1.3 至 2.2）。在患有 CKD 的成年人中，我们发现了 1q21.1、16p11.2、17q12 和 22q11.2 位点的复发性 GDs。17q12 GD（诊断为肾囊肿和糖尿病综合征）最常见，在 1：252 名患有 CKD 和糖尿病的患者中出现。在 PheWAS 中，透析和神经精神表型是与 GDs 最相关的。在 CRIC 参与者中，GDs 与血清镁降低、教育程度降低和死亡率升高有关。
在患有 CKD 的儿童和成人中均发现了未确诊的 GDs。在这些患者中鉴定 GDs 可以实现精确的基因诊断、提供预后信息并帮助在临床研究中分层风险。GDs 还可以为部分患者的肾脏疾病和合并症（如认知功能下降）提供分子解释。
