Genetic identification of inherited cystic kidney diseases for implementing precision medicine: a study protocol for a 3-year prospective multicenter cohort study

Abstract

Background Inherited cystic kidney disease is a spectrum of disorders in which clusters of renal cysts develop as the result of genetic mutation. The exact methods and pipelines for defining genetic mutations of inherited cystic kidney disease are not clear at this point. This 3-year, prospective, multicenter, cohort study was designed to set up a cohort of Korean patients with inherited cystic kidney disease, establish a customized genetic analysis pipeline for each disease subtype, and identify modifying genes associated with the severity of the disease phenotype. Methods/design From May 2020 to May 2022, we aim to recruit 800 patients and their family members to identify pathogenic mutations. Patients with more than 3 renal cysts in both kidneys are eligible to be enrolled. Cases of simple renal cysts and acquired cystic kidney disease that involve cyst formation as the result of renal failure will be excluded from this study. Demographic, laboratory, and imaging data as well as family pedigree will be collected at baseline. Renal function and changes in total kidney volume will be monitored during the follow-up period. Genetic identification of each case of inherited cystic kidney disease will be performed using a targeted gene panel of cystogenesis-related genes, whole exome sequencing (WES) and/or family segregation studies. Genotype-phenotype correlation analysis will be performed to elucidate the genetic effect on the severity of the disease phenotype. Discussion This is the first nationwide cohort study on patients with inherited cystic kidney disease in Korea. We will build a multicenter cohort to describe the clinical characteristics of Korean patients with inherited cystic kidney disease, elucidate the genotype of each disease, and demonstrate the genetic effects on the severity of the disease phenotype. Trial registration This cohort study was retrospectively registered at the Clinical Research Information Service (KCT0005580) operated by the Korean Center for Disease Control and Prevention on November 5th, 2020.

Clinical and genetic characteristics of Korean autosomal dominant polycystic kidney disease patients

“…However, the ESKD risk of the PKD1 IF indel and PKD1 NT patients were not different from PKD1 PT and the risk of death was no different between the four groups [ 39 ]. In the study, the reason why the prognosis of PKD1 NT is different from that of previous studies was not clarified and is expected to be verified through ongoing studies [ 42 ].…”

“…For those with variants of undetermined significance or no variants found by the gene panel, whole-exome sequencing will take place. A family segregation study will be performed to elucidate the cause of genotype-phenotype discordance, in-family severity discordance, or discordance between kidney and extra-renal manifestations [42]. [35] (n = 202)…”

“…Derangement of these genes mainly results in the dysfunction of primary cilium (ciliopathies) [ 41 ]. The iCKD include ADPKD, tuberous sclerosis complex, von Hippel-Lindau disease, autosomal dominant tubulointerstitial kidney disease, and pediatric diseases such as autosomal recessive polycystic kidney disease and nephronophthisis [ 42 ].…”

“…The ADPKD sub-cohort of the KNOW-CKD study showed that htTKV was a factor associated with lower eGFR [ 39 ]. This study was a cross-sectional analysis, it is thought that this relationship can be clarified through ongoing cohort studies [ 22 , 42 ].…”

Mayo imaging classification is a good predictor of rapid progress among Korean patients with autosomal dominant polycystic kidney disease: results from the KNOW-CKD study

“…A total of 162 patients had available genotype data from an inherited cystic kidney disease study [ 12 ]. Genomic DNA was extracted from whole blood and targeted exome sequencing was performed for 89 ciliopathy genes included in the gene panel.…”