Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease

García-González, Miguel A.; Jones, Jeffrey G.; Allen, Susan K.; Palatucci, Christopher M.; Batish, Sat Dev; Seltzer, William; Zheng, Lan; Allen, Erica; Qian, Feng; Lens, Xosé M.; Pei, York; Germino, Gregory G.; Watnick, Terry

doi:10.1016/j.ymgme.2007.05.004

Cited by 82 publications

(79 citation statements)

References 51 publications

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“…28,29 Magnetic resonance imaging (MRI), with its enhanced sensitivity for detecting small renal cysts, is also a promising modality 30 ; however, MRI may also detect a greater number of simple cysts as well as small cysts arising from ADPKD. Until the diagnostic utility of MRI in ADPKD is formally evaluated, the high diagnostic accuracy of ultrasonography, as well as its safety, accessibility, and comparatively low cost, will ensure its ongoing widespread use in ADPKD.…”

Section: Discussionmentioning

confidence: 99%

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Unified Criteria for Ultrasonographic Diagnosis of ADPKD

Pei

Obaji

Dupuis

et al. 2009

Journal of the American Society of Nephrology

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Individuals who are at risk for autosomal dominant polycystic kidney disease are often screened by ultrasound using diagnostic criteria derived from individuals with mutations in PKD1. Families with mutations in PKD2 typically have less severe disease, suggesting a potential need for different diagnostic criteria. In this study, 577 and 371 at-risk individuals from 58 PKD1 and 39 PKD2 families, respectively, were assessed by renal ultrasound and molecular genotyping. Using sensitivity data derived from genetically affected individuals and specificity data derived from genetically unaffected individuals, various diagnostic criteria were compared. In addition, data sets were created to simulate the PKD1 and PKD2 case mix expected in practice to evaluate the performance of diagnostic criteria for families of unknown genotype. The diagnostic criteria currently in use performed suboptimally for individuals with mutations in PKD2 as a result of reduced test sensitivity. In families of unknown genotype, the presence of three or more (unilateral or bilateral) renal cysts is sufficient for establishing the diagnosis in individuals aged 15 to 39 y, two or more cysts in each kidney is sufficient for individuals aged 40 to 59 y, and four or more cysts in each kidney is required for individuals Ն60 yr. Conversely, fewer than two renal cysts in at-risk individuals aged Ն40 yr is sufficient to exclude the disease. These unified diagnostic criteria will be useful for testing individuals who are at risk for autosomal dominant polycystic kidney disease in the usual clinical setting in which molecular genotyping is seldom performed.

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Section: Discussionmentioning

confidence: 99%

“…Alternatively, mutation screening of PKD1 and PKD2 can be performed. 28,29 Because the sensitivity for PKD2 mutation detection is at least 80% and most affected individuals with equivocal ultrasound results will have the milder PKD2 disease, gene-based testing is expected to provide reasonable diagnostic utility in this special target group.…”

Section: Discussionmentioning

confidence: 99%

Unified Criteria for Ultrasonographic Diagnosis of ADPKD

Pei

Obaji

Dupuis

et al. 2009

Journal of the American Society of Nephrology

Self Cite

626

448

View full text Add to dashboard Cite

show abstract

“…Gene-based molecular diagnostics are useful in this clinical scenario; however, a definitely pathogenic mutation only be identified may in up to two thirds of cases. As seen in TOR166, the interpretation of potentially pathogenic UCV remains uncertain as a result of a lack of a valid assay to determine their functional consequences (10,11).…”

Section: Discussionmentioning

confidence: 99%

“…Sequence analysis of PKD1 and PKD2 was performed in one clinically affected individual from each family using a commercial diagnostic service (Athena Diagnostics, Worcester, MA) (10,11). Briefly, genomic DNA was used as template for specific long-range PCR amplification of eight segments encompassing the entire PKD1 duplicated region.…”

Section: Gene-based Mutation Screeningmentioning

confidence: 99%

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Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease

Zhao¹,

Paterson²,

Zahirieh³

et al. 2008

Clinical Journal of the American Society of Nephrology

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Background and objectives: Gene-based mutation screening is now available and has the potential to provide diagnostic confirmation or exclusion of autosomal dominant polycystic kidney disease. This study illustrates its utility and limitations in the clinical setting. Design, setting, participants, & measurements: Using a molecular diagnostic service, genomic DNA of one affected individual from each study family was screened for pathologic PKD1 and PKD2 mutations. Bidirectional sequencing was performed to identify sequence variants in all exons and splice junctions of both genes and to confirm the specific mutations in other family members. In two multiplex families, microsatellite markers were genotyped at both PDK1 and PKD2 loci, and pair-wise and multipoint linkage analysis was performed.Results: Three of five probands studied were referred for assessment of renal cystic disease without a family history of autosomal dominant polycystic kidney disease, and two others were younger at-risk members of families with autosomal dominant polycystic kidney disease being evaluated as living-related kidney donors. Gene-based mutation screening identified pathogenic mutations that provided confirmation or exclusion of disease in three probands, but in the other two, only unclassified variants were identified. In one proband in which mutation screening was indeterminate, DNA linkage studies provided strong evidence for disease exclusion.Conclusions: Gene-based mutation screening or DNA linkage analysis should be considered in individuals in whom the diagnosis of autosomal dominant polycystic kidney disease is uncertain because of a lack of family history or equivocal imaging results and in younger at-risk individuals who are being evaluated as living-related kidney donors.

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Autosomal dominant polycystic kidney disease: Comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients

et al. 2012

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Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, is caused by mutations in PKD1 or PKD2. The molecular diagnosis of ADPKD is complicated by extensive allelic heterogeneity and particularly by the presence of six highly homologous sequences of PKD1 exons 1-33. Here, we screened PKD1 and PKD2 for both conventional mutations and gross genomic rearrangements in up to 700 unrelated ADPKD patients--the largest patient cohort to date--by means of direct sequencing, followed by quantitative fluorescent multiplex polymerase chain reaction or array-comparative genomic hybridization. This resulted in the identification of the largest number of new pathogenic mutations (n = 351) in a single publication, expanded the spectrum of known ADPKD pathogenic mutations by 41.8% for PKD1 and by 23.8% for PKD2, and provided new insights into several issues, such as the population-dependent distribution of recurrent mutations compared with founder mutations and the relative paucity of pathogenic missense mutations in the PKD2 gene. Our study, together with others, highlights the importance of developing novel approaches for both mutation detection and functional validation of nondefinite pathogenic mutations to increase the diagnostic value of molecular testing for ADPKD.

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Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease

Cited by 82 publications

References 51 publications

Unified Criteria for Ultrasonographic Diagnosis of ADPKD

Unified Criteria for Ultrasonographic Diagnosis of ADPKD

Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease: Comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients

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