Novel PKD1 and PKD2 mutations in Taiwanese patients with autosomal dominant polycystic kidney disease

Chang, Ming‐Yang; Chen, Hsiao-Mang; Jenq, Chang‐Chyi; Lee, Shen‐Yang; Chen, Yuming; Tian, Ya‐Chung; Chen, Yung‐Chang; Hung, Cheng‐Chieh; Fang, Ji‐Tseng; Yang, Chih-Wei; Wu-Chou, Yah-Huei

doi:10.1038/jhg.2013.91

Cited by 20 publications

(21 citation statements)

References 52 publications

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“…The mutation detection rate (90.0%) in our study (83.3% in PKD1 and 16.7% in PKD2 ) was comparable to previous studies using LR-PCR followed by nested PCR and direct sequencing in clinically well-defined large cohorts in Western countries [ 1 , 3 ]. Although the proportion of PKD2 mutations has been reported to be ~23% in Asian populations [ 16 , 17 ], PKD2 mutations accounted for 16.7% of the total mutations in our study subjects, comparable to data from Western countries (15.0%-16.2%) [ 1 , 3 ]. In contrast, a recent population-based study (Olmsted County population study) [ 24 ] and studies in an outpatient clinic setting [ 25 , 26 ] reported a higher PKD2 mutation detection rate than earlier studies, which recruited large families with a history of ERSD.…”

Section: Discussionsupporting

confidence: 83%

Identification of novel PKD1 and PKD2 mutations in Korean patients with autosomal dominant polycystic kidney disease

et al. 2014

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BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder. It is caused by mutations in the PKD1 and PKD2 genes, and manifests as progressive cyst growth and renal enlargement, resulting in renal failure. Although there have been a few studies on the frequency and spectrum of mutations in PKD1 and PKD2 in Korean patients with ADPKD, only exons 36–46, excluding the duplicated region, were analyzed, which makes it difficult to determine accurate mutation frequencies and mutation spectra.MethodsWe performed sequence analysis of 20 consecutive unrelated ADPKD patients using long-range polymerase chain reaction (PCR) to avoid pseudogene amplification, followed by exon-specific PCR and sequencing of the all exons of these two genes. Multiplex ligation-dependent probe amplification was performed in patients in whom pathogenic mutations in PKD1 or PKD2 were not identified by LR-PCR and direct sequencing to detect large genomic rearrangements.ResultsAll patients met the diagnostic criteria of ADPKD, and pathogenic mutations were found in 18 patients (90.0%), comprising 15 mutations in PKD1 and three in PKD2. Among 10 novel mutations, eight mutations were found in the PKD1 gene while two mutations were found in the PKD2 gene. Eight of 14 PKD1 mutations (57.1%) were located in the duplicated region.ConclusionsThis study expands the spectra of mutations in the PKD1 and PKD2 genes and shows that the mutation frequencies of these genes in Korean ADPKD patients are similar to those reported in other ethnicities. Sequence analysis, including analysis of the duplicated region, is essential for molecular diagnosis of ADPKD.

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Section: Discussionsupporting

confidence: 83%

Identification of novel PKD1 and PKD2 mutations in Korean patients with autosomal dominant polycystic kidney disease

et al. 2014

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“…Given the reduced cost of gene sequencing, such as targeted NGS, and the increasing number ADPKD patients whose phenotype is known, bringing PKD mutation types to clinical practice will likely reduce the economic cost of disease and reduce monitoring in patients destined to be symptom free while proactively increasing preventive monitoring for patients at high risk for progressive renal disease. In addition, defining the genetic mutation in ADPKD will better define the appropriate patient population for randomized clinical trials and develop new rationales for treatment using the molecular information obtained from locus and mutation detection810111213141516171819202122232425262728.…”

Section: Discussionmentioning

confidence: 99%

System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease

Jin

Chen

Liao

et al. 2016

Sci Rep

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder mainly caused by mutation in PKD1/PKD2. However, ethnic differences in mutations, the association between mutation genotype/clinical phenotype, and the clinical applicable value of mutation detection are poorly understood. We made systematically analysis of Chinese ADPKD patients based on a next-generation sequencing platform. Among 148 ADPKD patients enrolled, 108 mutations were detected in 127 patients (85.8%). Compared with mutations in Caucasian published previously, the PKD2 mutation detection rate was lower, and patients carrying the PKD2 mutation invariably carried the PKD1 mutation. The definite pathogenic mutation detection rate was lower, whereas the multiple mutations detection rate was higher in Chinese patients. Then, we correlated PKD1/PKD2 mutation data and clinical data: patients with mutation exhibited a more severe phenotype; patients with >1 mutations exhibited a more severe phenotype; patients with pathogenic mutations exhibited a more severe phenotype. Thus, the PKD1/PKD2 mutation status differed by ethnicity, and the PKD1/PKD2 genotype may affect the clinical phenotype of ADPKD. Furthermore, it makes sense to detect PKD1/PKD2 mutation status for early diagnosis and prognosis, perhaps as early as the embryo/zygote stage, to facilitate early clinical intervention and family planning.

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“…The major disadvantage of linkage analysis is that this method cannot be performed without a sufficient number of affected family members or when the proband is suspected of having a de novo mutation [31]. Although various gene-based screening methods are available for ADPKD molecular testing, such as the LRNS method, HRM method, and even next-generation sequencing methods, direct mutation sequencing remains the preferred choice for making a clinical diagnosis of ADPKD disease [12,14,16,32,33,34]. …”

Section: Discussionmentioning

confidence: 99%

“…Using these unique and lengthy amplification products as templates, nested PCR to amplify each individual exon was followed by sequencing [12,13,14]. Although a variety of methods are used to screen PKD1 mutations, such as high-resolution melt analysis [15], DNA high-performance liquid chromatography (DHPLC) [16], direct sequencing of long-range PCR products [17] and next-generation sequencing [18], long-range then nested PCR and sequencing (LRNS) is the predominant method in many laboratories.…”

Section: Introductionmentioning

confidence: 99%

Modification of PCR Conditions and Design of Exon-Specific Primers for the Efficient Molecular Diagnosis of PKD1 Mutations

Liu

Chen

Wei

et al. 2014

Kidney Blood Press Res

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Background/Aims: Autosomal-dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder caused by mutations in the PKD1 and PKD2 genes. Currently, long-range PCR followed by nested PCR and sequencing (LRNS) is the gold standard approach for PKD1 testing. However, LRNS is complicated by the high structural and sequence complexity of PKD1, which makes the procedure for amplification and analysis of PKD1 difficult. Methods: Here in, we modified the PCR conditions and designed primers for efficient and specific amplification of both the long-range and individual exons of PKD1. Results: Using the modified system, seven long-range fragments were specifically amplified using two distinct sets of conditions, and all individual exon PCR assays were easily performed using a touch-down PCR method. Seven pathogenic or likely pathogenic variants, including two novel truncated frameshift indels and two novel likely pathogenic missense mutations, were identified in eight unrelated patients with or without histories of ADPKD disease (one variant was observed in two unrelated patients). Using combined bioinformatics tools, two indeterminate missense variants were identified in two sporadic patients. Conclusion: Four novel PKD1 variants were identified in this study. We demonstrated that the modified LRNS method achieves high sensitivity and specificity for detecting pathogenic variants of ADPKD.

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Novel PKD1 and PKD2 mutations in Taiwanese patients with autosomal dominant polycystic kidney disease

Cited by 20 publications

References 52 publications

Identification of novel PKD1 and PKD2 mutations in Korean patients with autosomal dominant polycystic kidney disease

Identification of novel PKD1 and PKD2 mutations in Korean patients with autosomal dominant polycystic kidney disease

System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease

Modification of PCR Conditions and Design of Exon-Specific Primers for the Efficient Molecular Diagnosis of PKD1 Mutations

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