Sci Rep. 2019;9(1):16952.

Genetic Characteristics of Korean Patients with Autosomal Dominant Polycystic Kidney Disease by Targeted Exome Sequencing.

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제1저자 김현숙, 박혜인 · 교신저자 오윤규, 안규리

PMID 31740684 PMC6861305 DOI 10.1038/s41598-019-52474-1 IF 4.9 신장내과

소속 (13)

Department of Internal Medicine, Chuncheon Sacred Heart Hospital, Chuncheon, Korea.
Department of Internal Medicine, Kangnam Sacred Heart Hospital, Seoul, Korea.
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea.
Genomic Core Facility, Transdisciplinary Research and Collaboration Division, Translational Research Institute, and Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
National Assembly Futures Institute, Seoul, Korea.
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea.
Truewords Dialysis Clinic, Incheon, Korea.
Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea. yoonkyu@snu.ac.kr.
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea. curie@snu.ac.kr.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the main causes of end-stage renal disease (ESRD). Genetic information is of the utmost importance in understanding pathogenesis of ADPKD. Therefore, this study aimed to demonstrate the genetic characteristics of ADPKD and their effects on renal function in 749 Korean ADPKD subjects from 524 unrelated families. Genetic studies of PKD1/2 were performed using targeted exome sequencing combined with Sanger sequencing in exon 1 of the PKD1 gene and a multiple ligation probe assay. The mutation detection rate was 80.7% (423/524 families, 331 mutations) and 70.7% was novel. PKD1 protein-truncating (PKD1-PT) genotype was associated with younger age at diagnosis, larger kidney volume, lower renal function compared to PKD1 non-truncating and PKD2 genotypes. The PKD1 genotype showed earlier onset of ESRD compared to PKD2 genotype (64.9 vs. 72.9 years old, P < 0.001). In frailty model controlled for age, gender, and familial clustering effect, PKD2 genotype had 0.2 times lower risk for reaching ESRD than PKD1-PT genotype (p = 0.037). In conclusion, our results suggest that genotyping can contribute to selecting rapid progressors for new emerging therapeutic interventions among Koreans.

Figures

**Figure 1** Summary of identified mutations. (A) Prevalence of *PKD1* vs. *PKD2* mutations and cases of no mutation among 749 subjects (524 families); (B) Prevalence of *PKD1* vs. *PKD2* mutations among 630 subjects (423 families without NM families [n = 101]); (C) Frequency of each class in 423 families according to *PKD1/2* status; D. Frequency of each mutation class and grade in 524 families. Of the 749 subjects, 68% were classified as *PKD1*, 16% as *PKD2*, and 16% as no mutation (NM). Excluding NM subjects, 81% of the 630 subjects and 82% of the 423 families had *PKD1* mutations. The mutation classes in the 423 families that were obtained by excluding the 101 NM families from the original 524 families are shown in (C). In *PKD1*, frameshift mutations were the most common (39%), and in *PKD2*, nonsense mutations were the most common (52%). The prevalence of classes of variants (number of families that shared the same variants) among the 524 families was shown in (D). *Abbreviations*. DP, definitively pathogenic; HLP, highly likely pathogenic; LP, likely pathogenic; LN, likely neutral; I, indeterminate; NV, no variant.

**Figure 2** Cross-sectional analysis between age and log(htTKV) or eGFR (A). Scatter plot and trend line of log (htTKV) according to genotype. (B) Scatter plot and trend line of eGFR according to genotype. *PKD1*-PT genotype had a larger htTKV or lower eGFR than the *PKD1*-NT or *PKD2* genotypes. log(htTKV) increased rapidly with age in the *PKD1*-PT and *PKD2* genotypes, but it did so less intensely in the *PKD1*-NT genotype and those with NM. The *PKD1*-PT genotype also showed a steeper slope for eGFR than the other genotypes except *PKD1*-ID genotype. *Abbreviations*. htTKV, height-adjusted total kidney volume; eGFR, estimated glomerular filtration rate; *PKD1*-PT, *PKD1* protein-truncating; *PKD1*-NT, *PKD1* non-truncating; *PKD1*-ID, *PKD1* small in-frameshift indels.

**Figure 3** Renal outcomes and death according to type of *PKD1/2* mutation. (A) Survival analysis of ESRD progression. (B) Survival analysis of all-cause mortality. The median age of ESRD was 63.5 for PKD1-PT genotype, followed by 68.8 for PKD1-NT and 72.9 for PKD2. When *PKD1*-PT genotype was used as a reference, the *PKD2* genotype showed a 0.22 times lower HR of ESRD. The familial clustering effect was significant (P = 0.037). The incidence of death did not have difference according to genotypes. Abbreviations. ESRD, end-stage renal disease; *PKD1*-PT, *PKD1* protein-truncating; *PKD1*-NT, *PKD1* non-truncating; *PKD1*-ID, *PKD1* small in-frameshift indels; HR, hazard ratio; CI, confidence interval.

그림 출처: PubMed Central 공개 논문 (PMC6861305)

Comment · 정정

Erratum in Sci Rep. 2020 Apr 2;10(1):6033. doi: 10.1038/s41598-020-62489-8.

Conflict of interest statement

The authors declare no competing interests.

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