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

• Published in: Scientific reports Vol. 9; no. 1; p. 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: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-03-2019; Nature Publishing Group
• Subjects: 38/23; 38/77; 45/23; 631/208/514/2254; 692/4022/1585/1589; Cysts; Diagnosis; Exons; Female; Gene Duplication; Genetic screening; Genetic Testing - methods; Genetic Testing - standards; Genomes; Homology; Humanities and Social Sciences; Humans; Kidney diseases; Kidneys; Male; multidisciplinary; Mutation; Next-generation sequencing; Pedigree; Polycystic kidney; Polycystic Kidney, Autosomal Dominant - diagnosis; Polycystic Kidney, Autosomal Dominant - genetics; Pseudogenes; Renal function; Science; Science (multidisciplinary); TRPP Cation Channels - genetics; Ultrasound; Whole Genome Sequencing - methods; Whole Genome Sequencing - standards
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-40761-w

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.