期刊
KIDNEY INTERNATIONAL REPORTS
卷 8, 期 3, 页码 455-466出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ekir.2022.12.025
关键词
ADPKD; CKD; next generation sequencing; PKD; Sanger sequencing
This study established a multiplex PCR-based gene panel for rapid and cost-effective detection of disease-causing variants in patients with ADPKD. The results showed that combining clinical and genetic data had an impact on treatment decisions in 8.2% of patients with a molecular genetic diagnosis. This study is important for providing optimal patient counseling in ADPKD.
Introduction: Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure. Because of the heterogeneity in disease progression in ADPKD, parameters predicting future outcome are important. The disease-causing genetic variant is one of these parameters.Methods: A multiplex polymerase chain reaction (PCR)-based panel (MPP) was established for analysis of 6 polycystic kidney disease (PKD) genes (PKD1, PKD2, HNF1B, GANAB, DZIP1L, and PKHD1) in 441 patients with ADPKD. Selected patients were additionally sequenced using Sanger sequencing or a custom enrichment-based gene panel. Results were combined with clinical characteristics to assess the impact of genetic data on clinical decision-making. Variants of unclear significance (VUS) were considered diag-nostic based on a classic ADPKD clinical phenotype.Results: Using the MPP, disease-causing variants were detected in 65.3% of patients. Sanger sequencing and the custom gene panel in 32 patients who were MPP-negative revealed 20 variants missed by MPP, (estimated overall false negative rate 24.6%, false-positive rate 9.4%). Combining clinical and genetic data revealed that knowledge of the genotype could have impacted the treatment decision in 8.2% of patients with a molecular genetic diagnosis. Sequencing only the PKD1 pseudogene homologous region in MPP-negative patients resulted in an acceptable false-negative rate of 3.28%.Conclusion: The MPP yields rapid genotype information at lower costs and allows for simple extension of the panel for new disease genes. Additional sequencing of the PKD1 pseudogene homologous region is required in negative cases. Access to genotype information even in settings with limited resources is important to allow for optimal patient counseling in ADPKD.
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