Dataset Information

Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).

ABSTRACT: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed PKD1 and PKD2, in a large cohort of 440 unrelated Italian patients with ADPKD and 203 relatives by direct sequencing and MLPA. Molecular and detailed phenotypic data have been collected and submitted to the PKD1/PKD2 LOVD database. This is the first large retrospective study in Italian patients, describing 701 variants, 249 (35.5%) already associated with ADPKD and 452 (64.5%) novel. According to the criteria adopted, the overall detection rate was 80% (352/440). Novel variants with uncertain significance were found in 14% of patients. Among patients with pathogenic variants, in 301 (85.5%) the disease is associated with PKD1, 196 (55.7%) truncating, 81 (23%) non truncating, 24 (6.8%) IF indels, and in 51 (14.5%) with PKD2. Our results outline the high allelic heterogeneity of variants, complicated by the presence of variants of uncertain significance as well as of multiple variants in the same subject. Classification of novel variants may be particularly cumbersome having an important impact on the genetic counselling. Our study confirms the importance to improve the assessment of variant pathogenicity for ADPKD; to this point databasing of both clinical and molecular data is crucial.

SUBMITTER: Carrera P

PROVIDER: S-EPMC4976333 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).

Carrera Paola P Calzavara Silvia S Magistroni Riccardo R den Dunnen Johan T JT Rigo Francesca F Stenirri Stefania S Testa Francesca F Messa Piergiorgio P Cerutti Roberta R Scolari Francesco F Izzi Claudia C Edefonti Alberto A Negrisolo Susanna S Benetti Elisa E Alibrandi Maria Teresa Sciarrone MT Manunta Paolo P Boletta Alessandra A Ferrari Maurizio M

Scientific reports 20160808

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed PKD1 and PKD2, in a large cohort of 440 unrelated Italian patients with ADPKD and 203 relatives by direct sequencing and MLPA. Molecular and detailed phenotypic data have been collected and submitted to the PKD1/PKD2 LOVD database. This is the first large retrospective study in Italian patients, describing 701 variants, 249 (35.5%) already associated with ADPKD and 452 (64.5%) novel. Ac ...[more]

PMID: 27499327

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Project description:BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder, leading to end stage renal failure and kidney transplantation in its most serious form. The severity of the disease's manifestation depends on the genetic determination of ADPKD. The huge variability of different phenotypes (even within a single family) is not only modulated by the two main ADPKD genes (PKD1 and PKD2) but also by modifier genes and the whole genetic background.Case presentationThis is a report of an ADPKD family with co-inheritance of PKD1 and PKD2 pathogenic variants. The proband, with an extremely serious manifestation of ADPKD (the man was diagnosed in early childhood, and with end stage renal disease aged 23), underwent genetic analysis of PKD1 and PKD2, which revealed the presence of pathogenic mutations in both of these genes. The missense PKD2 mutation p.Arg420Gly came from the proband's father, with a mild ADPKD phenotype. The same mutation of the PKD2 gene and similar mild disease presentation were found in the proband's aunt (father's sister) and her son. The nonsense mutation p.Gln2196* within the PKD1 gene was probably inherited from the proband's mother, who died at the age of 45. It was only discovered post mortem, that the real cause of her death was kidney failure as a consequence of untreated ADPKD. Unfortunately, neither the DNA of the proband's mother nor the DNA of any other family members from this side of the pedigree were available for further examination. The proband underwent successful cadaveric kidney transplantation at the age of 24, and this replacement therapy lasted for the next 15 years.ConclusionsHere, we present a first case of bilineal ADPKD inheritance in the Czech Republic. This report highlights the significant role of modifier genes in genetic determination of ADPKD, especially in connection with seriously deteriorated disease phenotypes. In our case, the modifying role is probably mediated by the PKD2 gene.

Project description:BACKGROUND:Autosomal dominant polycystic kidney disease (ADPKD), a common of monogenetic disorder caused by the polycystic kidney disease-1 (PKD1) or PKD2 genes deficiency. In this study, we have re-analyzed a microarray dataset to generate a holistic view of this disease. METHODOLOGY:GSE7869, an expression profiling dataset was downloaded from the Gene Expression Omnibus (GEO) database. After quality control assessment, using GEO2R tool of GEO, genes with adjusted p-value???0.05 were determined as differentially expressed (DE). The expression profiles from ADPKD samples in different sizes were compared. Using CluePedia plugin of Cytoscape software, the protein-protein interaction (PPI) networks were constructed and analyzed by Cytoscape NetworkAnalyzer tool and MCODE application. Pathway enrichment analysis of clustered genes by MCODE with the high centrality parameters in PPI networks was performed using Cytoscape ClueGO plugin. Moreover, by Enrichr database, microRNAs (miRNAs) and transcription factors (TFs) targeted DE genes were identified. RESULTS:In this study to explore the molecular pathogenesis of kidney in ADPKD, mRNA expression profiles of cysts from patients in different sizes were re-analyzed. The comparisons were performed between normal with minimally cystic tissue (MCT) samples, MCTs with small cysts, and small cysts with large cysts. 512, 7024, and 655 DE genes were determined, respectively. The top central genes, e.g. END1, EGFR, and FOXO1 were identified with topology and clustering analysis. DE genes that were significantly enriched in PPI networks are critical genes and their roles in ADPKD remain to be assessed in future experimental studies beside miRNAs and TFs predicted. Furthermore, the functional analysis resulted in which most of them are expected to be associated with ADPKD pathogenesis, such as signal pathways that involved in cell growth, inflammation, and cell polarity. CONCLUSION:We have here explored systematic approaches for molecular mechanisms assay of ADPKD as a monogenic disease, which may also be used for other monogenetic diseases beside complex diseases to provide suitable therapeutic targets.

Dataset Information

Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).

Publications

Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).

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