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.
BackgroundAutosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of Polycystic Kidney Disease (PKD) and occurs at a frequency of 1/800 to 1/1000 affecting all ethnic groups worldwide. ADPKD shows significant intrafamilial phenotypic variability in the rate of disease progression and extra-renal manifestations, which suggests the involvement of heritable modifier genes. Here we show that the PKD1 gene can act as a disease causing and a disease modifier gene in ADPKD patients.MethodsClinical evaluation of a family with ADPKD was performed to diagnose and assess disease progression in each individual. PKD1 was genotyped in each individual by targeted sequencing.ResultsTargeted screening analysis showed that the patients with ADPKD in the family had the PKD1: p.Q2243X nonsense mutation. A more severe disease phenotype, in terms of estimated Glomerular Filtration Rate (eGFR) and total kidney volume, was observed in two patients where in addition to the mutation, they carried a novel PKD1 variant (p.H1769Y). Other patients from the same family carrying only the (p.Q2243X) mutation showed milder disease manifestations.ConclusionADPKD shows significant intrafamilial phenotypic variability that is generally attributed to other modifier genes. In this rare case, we have shown that a variant at PKD1, in trans with the PKD1 mutation, can also act as a modifier gene in ADPKD patients. Understanding the molecular mechanism through which the gene exerts its disease modifying role may aid our understanding of the pathogenesis of ADPKD.
Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal monogenic disease and characterized by bilateral accumulation of renal fluid-filled cysts leading to progressive renal volume enlargement and gradual impairment of kidney function which often resulting in ESRD. Kuwait could provide valuable genetic insight about ADPKD including intrafamilial phenotypic variation, given its large household size. This study aims to provide a comprehensive description of the pathogenic variants linked to ADPKD in the Kuwaiti population using multiple genetic analysis modalities and to describe and analyze the ADPKD phenotypic spectrum in term of kidney function, kidney volume and renal survival. Methods 126 ADPKD patients from 11 multiplex families and 25 singletons were recruited in the study. A combination of targeted next generation sequencing (tNGS), long range (LR) -PCR, Sanger sequencing and multiplex-ligation dependent probe amplification (MLPA) were utilized for genetic diagnosis. Clinical evaluation was conducted through Renal Function Test (RFT) and ultrasonographic kidney volume analysis. Results We identified 29 ADPKD pathogenic mutations from 36 families achieving an overall molecular genetic diagnostic rate of 112/126 (88.9%) including 29/36 (80.6%) in families. 28/36 (77.8%) of families had pathogenic mutations in PKD1, of which 17/28 (60.7%) were truncating, and 1/36 (2.8%) had a pathogenic variant in IFT140 gene. 20/29 (69%) of the identified ADPKD mutations were novel and described for the first time including a TSC2-PKD1 contiguous syndrome. Clinical analysis indicated that genetically unresolved ADPKD cases had no apparent association between kidney volume and age. Conclusion We describe for the first time the genetic landscape of ADPKD in Kuwait. The observed genetic heterogeneity underlining ADPKD along with the wide phenotypic spectrum reveals the level of complexity in disease pathophysiology. ADPKD genetic testing could improve care of patients through improving disease prognostication, guided treatment, as well as genetic counseling. However, to fulfill the potential of genetic testing, it is important to overcome the hurdle of genetically unresolved ADPKD cases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.