Improvement of Diagnostic Yield by an Additional Amplicon Module to Hybridization-Based Next-Generation Sequencing Panels.

Many approaches aimed at improving next-generation sequencing output for clinical purposes exist. However, sequencing gaps or misalignments for regions that are difficult to cover because of their low complexity or high homology still exist. Our aim was to improve the yield of sequencing data.

Ambulatory blood pressure and hypertension control in children with autosomal recessive polycystic kidney disease: clinical experience from two central European tertiary centres.

Objective: : Arterial hypertension is a common complication in patients with autosomal recessive polycystic kidney disease (ARPKD), occurring in 33-75% of children when measured by office blood pressure (OBP). Ambulatory blood pressure monitoring (ABPM) is a superior tool for investigating blood pressure relative to OBP. The aim of our study was to investigate the prevalence and control of hypertension in children with ARPKD based on ABPM.

Results of targeted next-generation sequencing in children with cystic kidney diseases often change the clinical diagnosis.

Cystic kidney diseases are a very heterogeneous group of chronic kidney diseases. The diagnosis is usually based on clinical and ultrasound characteristics and the final diagnosis is often difficult to be made. Next-generation sequencing (NGS) may help the clinicians to find the correct final diagnosis.

Mutational screening of inverted formin 2 in adult-onset focal segmental glomerulosclerosis or minimal change patients from the Czech Republic.

Background: Mutations in INF2 are frequently responsible for focal segmental glomerulosclerosis (FSGS), which is a common cause of end stage renal disease (ESRD); additionally, they are also connected with Charcot-Marie-Tooth neuropathy. INF2 encodes for inverted formin 2. This protein participates in regulation of the dynamics of the actin cytoskeleton, involving not only the polymerisation, but also the depolymerisation of filaments.

Bilineal inheritance of pathogenic PKD1 and PKD2 variants in a Czech family with autosomal dominant polycystic kidney disease - a case report.

Background: Autosomal 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.

[Gitelman´s syndrome as common cause of hypokalemia and hypomagnesemia].

The Gitelman syndrome (GS) is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis and presence of hypocalciuria and hypomagnesemia. It is one of the most common congenital "salt-wasting" tubulo-pathies, where the impairment of function of the Na+-Cl- cotransporter (NCCT) in the distal convoluted tubule is primary and hypokalemia secondary. Hypomagnesemia is caused by the impairment of magnesium reabsorption through TRPM6 channel which is located just by NCCT.

Molecular genetic analysis of PKHD1 by next-generation sequencing in Czech families with autosomal recessive polycystic kidney disease.

Background: Autosomal recessive polycystic kidney disease (ARPKD) is an early-onset form of polycystic kidney disease that often leads to devastating outcomes for patients. ARPKD is caused by mutations in the PKHD1 gene, an extensive gene that encodes for the ciliary protein fibrocystin/polyductin. Next-generation sequencing is presently the best option for molecular diagnosis of ARPKD.

Hereditary Renal Hypouricemia Type 1 and Autosomal Dominant Polycystic Kidney Disease.

Background: Renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid (UA) transport with severe complications, such as acute kidney injury. Type 1 is caused by a mutation in the SLC22A12 gene (URAT1) and type 2 in the SLC2A9 gene (GLUT9). In this article, the authors present a coexpression functional characterization of variants responsible for RHUC type 1 in a Czech family with polycystic kidney disease (PKD).

Synchronous gastric and sebaceous cancers, a rare manifestation of MLH1-related Muir-Torre syndrome.

Muir-Torre syndrome (MTS), a rare variant of the hereditary non polyposis colorectal cancer syndrome, is an autosomal dominant genodermatosis characterised by coincidence of sebaceous gland neoplasms (sebaceous adenoma, epithelioma, or carcinoma) and at least one internal malignancy. The underlying cause of MTS is a germline mutation in DNA mismatch repair genes MSH2, MLH1 and MSH6. We report the case of a 52-year-old caucasian woman with the development of metachronous colon cancer at the age of 38 years, uterine cancer at the age of 43 years, and unique occurrence of synchronous gastric and sebaceous carcinomas related to germline point mutation c.

Novel mutations of PKD genes in the Czech population with autosomal dominant polycystic kidney disease.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder caused by mutation in either one of two genes, PKD1 and PKD2. High structural and sequence complexity of PKD genes makes the mutational diagnostics of ADPKD challenging. The present study is the first detailed analysis of both PKD genes in a cohort of Czech patients with ADPKD using High Resolution Melting analysis (HRM) and Multiplex Ligation-dependent Probe Amplification (MLPA).

Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease that results in renal failure. ADPKD is a systemic disorder with cysts and connective tissue abnormalities involving many organs. ADPKD caused by mutations in PKD1 gene is significantly more severe than the cases caused by PKD2 gene mutations.

Gitelman syndrome as a cause of psychomotor retardation in a toddler.

Introduction: Gitelman syndrome (GS) is a very rare autosomal recessive tubulopathy due to loss-of-function or mutation in solute carrier family12, member 3 gene (SLC12A3 gene) encoding thiazide-sensitive NaCl co-transporter in the distal convoluted tubule, leading to hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria and low-to-normal blood pressure. Clinical signs are mostly secondary to chronic hypokalemia and include dizziness, fatigue, constipation and weakness. Patients can also present with muscle cramps, tetany, fatigue and convulsions due to severe metabolic alkalosis or hypomagnesemia.

Novel mutations of the APC gene and genetic consequences of splicing mutations in the Czech FAP families.

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome with almost 100 % risk of colorectal cancer. The typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by extracolonic manifestations, later onset and lower number of polyps in colon is characteristic of an attenuated form (AFAP). We analyzed the APC gene for germline mutations in 90 FAP/AFAP patients.

Cryptic chromosomal rearrangements in children with idiopathic mental retardation in the Czech population.

Aims: The aim of our study was to scan for cryptic rearrangements using the multiplex ligation probe amplification method in a cohort of 64 probands with mental retardation or developmental delays in combination with at least one of the following symptoms: hypotonia after birth, congenital anomalies, or face dysmorphisms; but without a positive cytogenetic finding. The study contributes to the knowledge of microdeletion syndromes and helps disclose their natural phenotypic variability.

Results: In total, 10 positives (16%) were detected, particularly 3 duplications (Xpter-p22.

New mutations in the PKD1 gene in Czech population with autosomal dominant polycystic kidney disease.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. The disease is caused by mutations of the PKD1 (affecting roughly 85% of ADPKD patients) and PKD2 (affecting roughly 14% of ADPKD patients) genes, although in several ADPKD families, the PKD1 and/or PKD2 linkage was not found. Mutation analysis of the PKD1 gene is complicated by the presence of highly homologous genomic duplications of the first two thirds of the gene.

Genotype-phenotype correlation in children with autosomal dominant polycystic kidney disease.

Adults with autosomal dominant polycystic kidney disease (ADPKD) and PKD1 mutations have a more severe disease than do patients with PKD2 mutations. The aim of this study was to compare phenotypes between children with mutations in the PKD1/PKD2 genes. Fifty PKD1 children and ten PKD2 children were investigated.

Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects.

Background: Germline mutations in the adenomatous polyposis gene (APC) result in familial adenomatous polyposis (FAP). FAP is an autosomal dominantly inherited disorder predisposing to colorectal cancer. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extracolonic manifestations.

Genetic analysis of Gitelman syndrome patients from the Czech Republic and Slovakia--three novel mutations found.

Background: To investigate the genetic cause of inherited hypokalemic metabolic alkalosis associated with Gitelman's syndrome, we searched for mutations in the SLC12A3 gene (thiazide-sensitive NaCl cotransporter) among a set of patients from the Czech Republic and Slovakia.

Methods: We collected blood samples of patients from 16 families with characteristic clinical features. DNA was analyzed for mutation detection with SSCP and subsequent sequencing.

PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis.

Methods: We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them.

PKD2 mutations in a Czech population with autosomal dominant polycystic kidney disease.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous and caused by mutations in at least three different loci. Based on linkage analysis, mutations in the PKD2 gene are responsible for approximately 15% of the cases. PKD2-linked ADPKD is supposed to be a milder form of the disease, its mean age of end-stage renal failure (ESRF) approximately 20 years later than PKD1.

Influence of the endothelial nitric oxide synthase polymorphism on the progression of autosomal dominant polycystic kidney disease and IgA nephropathy.

Background: The reason of variability of clinical course and progression to end-stage renal failure (ESRF) of two widespread chronic nephropathies--autosomal dominant polycystic kidney disease (ADPKD) and IgA nephropathy (IGAN) is not clear. The endothelial dysfunction is considered in the number of factors possibly influencing the prognosis of these nephropathies. Our study tried to verify the hypothesis that endothelial nitric oxide synthase (ecNOS) gene polymorphisms in intron 4 could have some relevance to the progression of ADPKD and/or IgA nephropathy.

Influence of the endothelial nitric oxide synthase polymorphism on the progression of autosomal dominant polycystic kidney disease and IgA nephropathy.

Background: The reason of variability of clinical course and progression to end-stage renal failure (ESRF) of two widespread chronic nephropathies-autosomal dominant polycystic kidney disease (ADPKD) and IgA nephropathy (IGAN) is not clear. The endothelial dysfunction is considered in the number of factors possibly influencing the prognosis of these nephropathies. Our study tried to verify the hypothesis that endothelial nitric oxide synthase (ecNOS) gene polymorphisms in intron 4 could have some relevance to the progression of ADPKD and/or IgA nephropathy.

Endothelial nitric oxide synthase affects the progression of autosomal dominant polycystic kidney disease.

Background/aim: The phenotypic variability of autosomal dominant polycystic kidney disease (ADPKD) cannot be explained only by various mutations of two known genes (PKD1 and PKD2), but the influence of other unknown factors should also be considered. Impairment of endothelial function has been observed in ADPKD patients. Our study tried to verify the hypothesis that endothelial nitric oxide synthase (ecNOS) gene polymorphisms in intron 4 could have some relevance to the progression of ADPKD.