PKD1 Duplicated regions limit clinical Utility of Whole Exome Sequencing for Genetic Diagnosis of Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited monogenic renal disease characterised by the accumulation of clusters of fluid-filled cysts in the kidneys and is caused by mutations in PKD1 or PKD2 genes. ADPKD genetic diagnosis is complicated by PKD1 pseudogenes located proxima...

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Bibliographic Details
Published in:Scientific reports 2019-03, Vol.9 (1), p.4141, Article 4141
Main Authors: Ali, Hamad, Al-Mulla, Fahd, Hussain, Naser, Naim, Medhat, Asbeutah, Akram M, AlSahow, Ali, Abu-Farha, Mohamed, Abubaker, Jehad, Al Madhoun, Ashraf, Ahmad, Sajjad, Harris, Peter C
Format: Article
Language:English
Subjects:
Cysts
Diagnosis
Exons
Female
Gene Duplication
Genetic screening
Genetic Testing - methods
Genetic Testing - standards
Genomes
Homology
Humans
Kidney diseases
Male
Mutation
Next-generation sequencing
Pedigree
Polycystic kidney
Polycystic Kidney, Autosomal Dominant - diagnosis
Polycystic Kidney, Autosomal Dominant - genetics
Pseudogenes
Renal function
TRPP Cation Channels - genetics
Ultrasound
Whole Genome Sequencing - methods
Whole Genome Sequencing - standards
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Summary:Autosomal dominant polycystic kidney disease (ADPKD) is an inherited monogenic renal disease characterised by the accumulation of clusters of fluid-filled cysts in the kidneys and is caused by mutations in PKD1 or PKD2 genes. ADPKD genetic diagnosis is complicated by PKD1 pseudogenes located proximal to the original gene with a high degree of homology. The next generation sequencing (NGS) technology including whole exome sequencing (WES) and whole genome sequencing (WGS), is becoming more affordable and its use in the detection of ADPKD mutations for diagnostic and research purposes more widespread. However, how well does NGS technology compare with the Gold standard (Sanger sequencing) in the detection of ADPKD mutations? Is a question that remains to be answered. We have evaluated the efficacy of WES, WGS and targeted enrichment methodologies in detecting ADPKD mutations in the PKD1 and PKD2 genes in patients who were clinically evaluated by ultrasonography and renal function tests. Our results showed that WES detected PKD1 mutations in ADPKD patients with 50% sensitivity, as the reading depth and sequencing quality were low in the duplicated regions of PKD1 (exons 1-32) compared with those of WGS and target enrichment arrays. Our investigation highlights major limitations of WES in ADPKD genetic diagnosis. Enhancing reading depth, quality and sensitivity of WES in the PKD1 duplicated regions (exons 1-32) is crucial for its potential diagnostic or research applications.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-40761-w