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Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the modulation of lipid metabolism as a critical negative regulator of hepatic low-density lipoprotein receptor (LDLR) levels and circulating low-density lipoprotein (LDL) clearance. Numerous gain-of-function (GOF) mutations in PCSK9 have been identified as causing familial hypercholesterolemia (FH) by reducing LDLR levels, and loss-of-function (LOF) mutations associated with a hypercholesterolemia phenotype protective against atherosclerosis. PCSK9 represents an example of successful translational research resulting in the identification of PCSK9 as a major drug target for a lipid-lowering therapy. To explore the genetic constitution of PCSK9 and its biologic role, in this review, we summarize the current evidence of clinically significant PCSK9 genetic variants involved in lipid metabolism as well as emphasize the importance of PCSK9 inhibition for the improvement of cardiovascular outcomes by conducting a meta-analysis of the available data on the incidence of cardiovascular disease events., (© 2024. The Author(s).)

Background: Hypertrophic cardiomyopathy is a heterogeneous myocardial disease. Mutations appearing in several genes might be a potential cause of the disease. The aim of the study was to analyze selected exons of the sarcomeric and non-sarcomeric genes, with the purpose to identify potential candidate genetic variants and to understand etiopathogenetic mechanisms of hypertrophic cardiomyopathy in East Slovak patients., Methods: This study recruited 23 unrelated patients with hypertrophic cardiomyopathy, namely, 13 men and 10 women (mean age of 58.09±15.82 years) and 25 healthy controls in order to determine the candidate sequence variants, in the selected exons of six cardiomyopathy genes (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2), by conventional capillary-based Sanger sequencing method and standard protocols., Results: Molecular genetic results confirmed the presence of 43 sequence variants in the selected exons of six cardiomyopathy genes, 58.14% of detected variants were novel. The majority of detected sequence variants were confirmed within exon 23 of MYH7 gene. Only 11 genetic alterations were predicted to be potentially pathogenic., Conclusions: In our study, we identified known and novel sequence variants in 23 unrelated patients with hypertrophic cardiomyopathy, but we did not observe any strong mutation hotspot. The results of our study assumed that exon 23 of MYH7 gene can be in potential affinity to hypertrophic cardiomyopathy in our cohort of patients. The sequence variants identified in this study may be further investigated in order to determine their functions in disease pathogenesis and improve management, diagnosis, and treatment in Slovak patients., (© 2017 Wiley Periodicals, Inc.)

Background: As the leading cause of congestive heart failure, cardiomyopathy represents a heterogenous group of heart muscle disorders. Despite considerable progress being made in the genetic diagnosis of cardiomyopathy by detection of the mutations in the most prevalent cardiomyopathy genes, the cause remains unsolved in many patients. High-throughput mutation screening in the disease genes for cardiomyopathy is now possible because of using target enrichment followed by next-generation sequencing. The aim of the study was to analyze a panel of genes associated with dilated or hypertrophic cardiomyopathy based on previously published results in order to identify the subjects at risk., Methods: The method of next-generation sequencing by IlluminaHiSeq 2500 platform was used to detect sequence variants in 16 individuals diagnosed with dilated or hypertrophic cardiomyopathy. Detected variants were filtered and the functional impact of amino acid changes was predicted by computational programs., Results: DNA samples of the 16 patients were analyzed by whole exome sequencing. We identified six nonsynonymous variants that were shown to be pathogenic in all used prediction softwares: rs3744998 (EPG5), rs11551768 (MGME1), rs148374985 (MURC), rs78461695 (PLEC), rs17158558 (RET) and rs2295190 (SYNE1). Two of the analyzed sequence variants had minor allele frequency (MAF)<0.01: rs148374985 (MURC), rs34580776 (MYBPC3)., Conclusion: Our data support the potential role of the detected variants in pathogenesis of dilated or hypertrophic cardiomyopathy; however, the possibility that these variants might not be true disease-causing variants but are susceptibility alleles that require additional mutations or injury to cause the clinical phenotype of disease must be considered., (© 2017 Wiley Periodicals, Inc.)

Objectives: To clarify the connection between two selected mononucleotide polymorphisms (rs4957014 and rs3756712) in programmed cell death gene 6 (PDCD6) and endometriosis development risk in patients belonging to the majority population of Slovakia., Methods: From all women involved in the research a buccal DNA sample was taken. A genetic analysis of selected polymorphisms was implemented using Real-time PCR method. Variance in allelic and genotype frequencies was statistically evaluated between the controlgroup and the group of patients., Results: The analysed group consisted of 52 women suffering from endometriosis and the control group of 63 women. Variant G allele frequency in the group of patients in case of polymorphism rs3756712 had a value of 0.42 and in the control group 0.29; that represents its statistically and significantly higher occurrence in the group of patients suffering from endometriosis (p = 0.029 and OR = 1.833). Presence of G allele is related to almost 1.9 times higher risk of endometriosis development., Conclusion: Achieved results show that polymorphism rs3756712 is significantly associated with the risk of endometriosis development in Slovak women. Polymorphism rs4957014 did not show any connection with development of endometriosis (Tab. 5, Ref. 10).

Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury. Type 1 and 2 are caused by loss-of-function mutations in the SLC22A12 and SLC2A9 gene, respectively. A cohort of 881 randomly chosen ethnic Roma from two regions in Eastern Slovakia and two regions in the Czech Republic participated. Genomic DNA was isolated from buccal swabs and/or from blood samples. The c.1245&#95;1253del and c.1400C>T genotypes were determined using polymerase chain reaction with allele-specific primers in a multiplex arrangement and/or direct sequencing of exon 7 and 9. Allele frequencies and genotypes were tested for Hardy-Weinberg equilibrium using the Chi-square test. 25 subjects were heterozygous and three were homozygous for the c.1245&#95;1253del, while 92 subjects were heterozygous and two were homozygous for the c.1400C>T. Moreover, two participants were compound heterozygotes. Frequencies of the c.1245&#95;1253del and c.1400C>T variants were 1.87 and 5.56 %, respectively. Our finding confirms an uneven geographical and ethnic distribution of SLC22A12 mutant variants. We found that the c.1245&#95;1253del and c.1400C>T variants were present in the Czech and Slovak Roma population at unexpectedly high frequencies. Renal hypouricemia should be kept in mind during differential diagnostic on Roma patients with low serum uric acid concentrations.

Aims: Hereditary as well as acquired thrombophilia is associated with a higher incidence of severe obstetric complications such as preeclampsia, spontaneous pregnancy loss, placental abruption, and fetal growth retardation. The aim of our study was to examine the association of selected thrombophilic polymorphisms (factor V Leiden, MTHFR C677T, and MTHFR A1298C) with pregnancy complications in the Slovak majority population and the Roma (Gypsy) ethnic population. The study included 354 women; 120 patients and 105 controls from the Slovak majority population, 50 patients and 79 controls from the Slovak Roma population. Genotyping was performed by the real-time polymerase chain reaction method using TaqMan(®) MGB probes., Results: A statistically significant higher frequency of factor V Leiden (p=0.001, odds ratio [OR]=5.9) and MTHFR C677T polymorphism (p=0.011, OR=1.7) was observed in the Slovak majority patient group compared to the control group. The incidence of MTHFR A1298C polymorphism between patients and controls did not differ significantly. None of the three polymorphisms studied was in association with pregnancy complications in the group of Roma women., Conclusions: Our study has confirmed the variable distribution of selected thrombophilic polymorphisms in different ethnic groups as well as their various effects on the clinical phenotype.

Autosomal recessive forms of Charcot-Marie-Tooth disease (CMT) account for less than 10 % of all CMT cases, but are more frequent in the populations with a high rate of consanguinity. Roma (Gypsies) are a transnational minority with an estimated population of 10 to 14 million, in which a high degree of consanguineous marriages is a generally known fact. Similar to the other genetically isolated founder populations, the Roma harbour a number of unique or rare autosomal recessive disorders, caused by "private" founder mutations. There are three subtypes of autosomal recessive CMT with mutations private to the Roma population: CMT4C, CMT4D and CMT4G. We report on the molecular examination of four families of Roma origin in Slovakia with early-onset demyelinating neuropathy and autosomal recessive inheritance. We detected mutation p.R148X (g.631C>T) in the NDRG1 (NM&#95;006096.3) gene in two families and mutation g.9712G>C in the HK1 (NM&#95;033498) gene in the other two families. These mutations cause CMT4D and CMT4G, respectively. The success of molecular genetic analysis in all families confirms that autosomal recessive forms of CMT caused by mutations on the NDRG1 and HK1 genes are common causes of inherited neuropathies among Slovak Roma. Providing genetic analysis of these genes for patients with Roma origin as a common part of diagnostic procedure would contribute to a better rate of diagnosed cases of demyelinating neuropathy in Slovakia and in other countries with a Roma minority.

Philadelphia chromosome (Ph) is a characteristic chromosomal marker that is associated with chronic myelogenous leukemia (CML). Philadelphia chromosome in bone marrow cells in patients with suspected diagnosis of CML in the Presov region (1995-2004) was detected in 94.4 % of cases. In one patient a complex translocation involving the chromosomes 8, 9 and 22 was identified. One patient has showed extra numerical and structural chromosomal aberrations. The mosaic karyotype of Ph chromosome was found in 5.9 % of cases. The conventional cytogenetic analysis remains the standard method for the purpose of diagnosis and monitoring of the therapeutic response and minimal residual disease in patients with chronic myeloid leukemia (Tab. 1, Fig. 1, Ref. 18). Full Text (Free, PDF) www.bmj.sk.

Prenatal genetic diagnostics is a part of prenatal care. Prenatal karyotyping is used to identify major genetic and congenital abnormalities in a developing fetus. In the Presov region (Slovakia) in 1999-2004 370 amniotic fluid samples were analysed by G-banding. Abnormal karyotypes were detected in 3.8% of samples. A karyotype using classical banding methods is the only fully informative method able to detect all chromosomal abnormalities. Identification of fetal abnormal chromosomes in high risk pregnancies allows proper pediatric and obstetric managment of the cases as well as genetic counselling (Tab. 1, Fig. 2, Ref. 5).