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Publicly available genome-wide data, sequenced from 2730 ancient human samples were analyzed for genetic predisposition to malignancy. The temporal and spatial incidence of risk variants for cancer diseases in ancient genomes was recorded, allowing for estimates of their frequencies in ancient human communities. We identified 55 risk alleles associated with oncological conditions in the screened ancient samples. For further analysis, we selected three variants conclusively deemed to entail pathogenic effect, the VHL gene's rs28940298, the TP53 gene's rs78378222 and the BRCA2 gene's rs11571833. The contemporary population frequency of these three variants is lower, or similar, to their estimated frequency in ancient human communities, indicating that they might have been subject to negative selection. This is also suggested by their temporal dynamics during the last 10000 years, which show an overall temporal decrease in population frequency. The oldest samples in which these three variants were established testify their ancient origin, including the presence of TP53 gene's rs78378222 variant in 50000 BP old Neanderthal and Denisovan genomes. Our results demonstrate the presence of cancer-causing mutations in ancient human communities and suggest that they differed in frequency among ancient populations as they do among contemporary ones. Data on germline mutations in tumour suppressor genes in ancient human genomes are scarce and their historic prevalence gives insights into the evolution of predisposition to cancer disease and hence helps advance paleogenomic medicine. [ABSTRACT FROM AUTHOR]

In an effort to better understand the complex genetic background of Alzheimer's disease (AD) we performed high-coverage whole-exome sequencing of a DNA pool assembled of 66 Bulgarian AD patients. We focused our analysis on genes demonstrated to have association with AD in previous studies, i.e. PSEN1, PSEN2, APP, APOE, TREM2, HFE, CLU and CR1. In these genes, we established six pathogenic/likely pathogenic variants in the sequenced pool, three common and three rare. Two of these variants showed statically non-significant difference between Bulgarian AD patients and Bulgarian control exomes, the hemochromatosis variant rs104894002 (HFE) and rs7412 (APOE), which, notwithstanding its pathogenicity score, has putative protective role against AD. Three of the remaining four pathogenic/likely pathogenic variants were estimated to significantly differ in frequency between the analyzed AD patient pool and controls. These are the rs429358 (APOE) polymorphism, a well-established risk factor for Alzheimer's disease, the rs28936380 (PSEN2) and rs104894002 (TREM2), also ascertained to be associated with AD. The performed study validates the role of three pathogenic/likely pathogenic variants in AD related genes in the multifaceted genetic etiology of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Contemporary genetic methods have not yet solved the 'missing heritability' problem of complex diseases such as Alzheimer's disease (AD). The impact of rare or less common variation on human complex diseases and traits remains to date barely investigated. In this study rare population variants detected using whole-exome sequencing were employed to examine how molecular pathways are prioritized in four groups: Alzheimer's disease (AD) patients, Frontotemporal dementia (FTD) patients, young and healthy individuals and centenarians. The set of prioritized genes in AD patients associated with Semaphorin interactions pathways, contrasting with the results of the other groups. We identified rare pathogenic, likely pathogenic and variants of unknown significance in these prioritized genes in AD patients. The results of this study offer evidence that semaphorin pathways play a role in AD genetic etiology. [ABSTRACT FROM AUTHOR]

Targeted therapy with tyrosine kinase inhibitors (TKIs) was introduced for the suppression of BCR-ABL fusion protein in chronic myelogenic leukemia (CML) more than 50 years ago. The introduction of TKI was an elegant way to gain control over the disease and opened a horizon to the development of new and safer drugs to better manage the disease progression in CML patients. Although Imatinib (the first TKI) was highly effective for the treatment of CML, the lack of response in some patients and the development of resistance led to the introduction of a second-generation TKI, like Nilotinib (Tasigna®). This study aimed to show the molecular response to Nilotinib after a long-term monitoring of CML patients. We analyzed the molecular response rate of twenty-seven CML patients admitted to the Hematology Ward. All of them were subjected to multiple control measurements of Philadelphia chromosome once in at least three months' period between January 2017 and March 2020. All patients showed a remarkable decrease in the level of the fusion gene's expression. The highest drop in the expression level was detected after the first dose admission. Some of the patients even reached an expression of BCR-ABL below the detection limit and it was maintained stably low during further examinations. In our patients with CML, Nilotinib resulted in prolonged and deep molecular response. The expression level of BCR-ABL fusion gene showed a substantial decrease immediately after Nilotinib treatment, revealed as early as the third month of therapy. [ABSTRACT FROM AUTHOR]

Overweight and obesity are serious and an ever-growing problem in modern society. It is a major risk factors for a number of chronic diseases, including type 2 diabetes, cardiovascular diseases and cancer. Obesity is a complex condition resulting from the interaction of a range of genetic and environmental factors. The aim of this study was to identify genetic markers predisposing to, and molecular pathways associated with, obesity in Bulgarian healthy individuals. Whole-exome sequencing was performed on two DNA pools: one constructed of 32 Bulgarian centenarians and one of 61 young healthy individuals, both with normal BMI, and allele frequencies of detected variants were estimated for each pool. Centenarians were chosen as their exome could be considered 'golden standard' for health and longevity, including being free of genetic variants predisposing to obesity. The young individuals group was chosen so variants predisposing to obesity after adolescence can be evaluated when compared to the centenarians. Of all variants designated to be associated with obesity by the database DisGeNET, only 17% were discovered in the studied pools. Using the platform ToppGene, we identified three over-represented pathways based on genes with variants showing significant prelevance in allele frequency in the young individuals group. These three pathways were all G-protein coupled receptor associated pathways: the GPCR ligand binding pathway, the G alpha (s) signalling events pathway and the Class A/1 (Rhodopsin-like receptors) pathway. Understanding the genetic etiology of obesity in different populations is instrumental in developing pharmacological targets for population-specific obesity therapies. [ABSTRACT FROM AUTHOR]

Many bladder cancer (BC) patients with early disease are asymptomatic and diagnosed at advanced stage when the therapeutic options are limited. This necessitates the development of reliable predictive molecular biomarkers that will ensure a positive therapeutic response in every patient. The aim of this study was to screen for alterations in gene expression levels related to drug sensitivity and resistance that may be further explored as potential predictive therapeutic biomarkers. Gene expression analysis of the 168 genes from two panels for Cancer drug resistance and metabolism (PAHS004) and Cancer Drug Targets (PAHS507z) was performed. A total of 47 transitorial cell bladder cancer samples of stage pTa, pT1, pT2 were investigated using the pooling method, which allows reducing the effect of biological variation and detecting only significant expression changes. Differential gene expression was calculated using the ΔΔCt method with GPDH as a housekeeping gene. The 4.0-fold change in gene expression was used as the cut-off threshold to determine upregulation or downregulation compared to normal bladder tissue (negative control). Significance of the differences in the expression profiles was assessed by nonparametric one-way analysis of variance (ANOVA) with Dunn's multiple comparison tests and Mann-Witney test. We demonstrated a correlation of tumor invasion and several up-regulated genes related to chemotherapy resistance. For the first time, this study demonstrated overexpression of CDK8, CDK9, FIGF, HDAC11, IGF1 and PDGFRA genes in muscle-invasive bladder carcinomas. These genes and their proteins could be used as potential biomarkers for bladder cancer progression or prospective therapeutic targets. [ABSTRACT FROM AUTHOR]

Coronary heart disease (CHD) is a major cause of mortality and morbidity in Europe. CHD is usually caused by atherosclerosis. Despite extensive studies that have identified a large number of genetic variants, strong evidence of association with CHD are not easily replicable in different populations. Two DNA pools were constructed: one with 32 Bulgarian centenarians and one with 61 young healthy Bulgarian individuals. The pools were whole-exome sequenced and variants were annotated and quality filtered (89,810 filtered variants). Allele frequencies were estimated and Fisher's exact test was used to evaluate the significance of allele frequency differences between the two pools. Two publicly available databases, Ensembl and DisGeNET, were used as a source of 2025 CHD-associated variants (CHD-AVs). These single nucleotide polymorphisms were screened in our data and 158 variants in 133 genes were found. ToppGene pathways analysis of genes called in both pools discovered participation of 37 genes in 9 significantly over-represented pathways. Eight variants in these 37 genes have significantly higher frequency in young individuals, and are nominated for CHD association. Variants called only in the young individuals pool (13 variants) are also nominated for association with CHD. Based on sufficiently unambiguous literature data, from the nominated variants, we prioritize five as associated with CHD in the studied Bulgarian sample. Centenarian genomes can be used to provide additional information regarding the clinical relevance of genetic variants reported as associated with CHD. [ABSTRACT FROM AUTHOR]

Preimplantation genetic testing (PGT) is presently the only option available for detecting genetic conditions in embryos created through in vitro fertilization (IVF) prior to implantation. Thus PGT eliminates the dilemma of pregnancy termination following unfavorable prenatal diagnosis test results. Complex chromosome rearrangements (CCRs), although very rarely reported in humans, represent a significant clinical problem for their carriers. CCRs include at least three breakpoints affecting two or more chromosomes. In three-breakpoint translocations, theoretically sixty-four different chromosomal sets are produced. Only two of them will be balanced and will lead to the birth of a phenotypically normal child. Therefore, CCR carriers are at increased risk of chromosomally unbalanced conceptions, resulting in spontaneous abortions or birth of offspring with intellectual disability and/or congenital anomalies. The reproductive options before such families are: natural conception followed by prenatal diagnosis; donor gametes; adoption or PGT. In this paper we discuss the current state of the PGT field and report on two PGT-cases for CCR in families with infertility and recurrent pregnancy losses. The families underwent IVF-PGT on day 3 and day 5 embryos and whole genome microarray analysis. [ABSTRACT FROM AUTHOR]

11β-Hydroxylase deficiency is the second most common enzyme disorder after 21-hydroxylase deficiency causing congenital adrenal hyperplasia (CAH11β). In females, the clinical phenotype of CAH11β classic forms is associated with ambiguous genitalia, virilization and hypertension, while most common complaints in milder non-classic forms include hirsutism, acne, menstrual disturbances, and infertility. Herein, we present clinical and genetic characteristics of an adult woman with 11β-hydroxylase deficiency, hypertension and infertility; she has been followed up from her first pregnancy to her early menopause. Genetic analyses of the patient revealed a compound-heterozygosity due to two variants in the CYP11B1 gene p.Val316Met and p.Asp480ThrfsTer2. Both mutations have not been previously reported as pathogenic in the literature. Emerging questions concerning the clinical management, fertility potential, mineral corticoid abnormalities and perimenopausal transition in patients with non-classic CAH11β have also been briefly discussed. The presented case of an adult woman with CAH11β shows that the proper diagnosis and close monitoring of patients with different CAH forms might ensure good therapy adherence and successful fertility. [ABSTRACT FROM AUTHOR]

Early infantile epileptic encephalopathy (EIEE) is a disorder with variable genetic heterogeneity. Symptoms are mostly presented with generalised epileptic seizures with an infantile onset and progressive neurodevelopmental delay. Early infantile epileptic encephalopathy13 is caused by mutations in the SCN8A gene, which encodes the neuronal voltage-gated sodium channel α subunit (Nav1.6) and plays a major role in neuronal excitability. Describing the wide clinical variability of previously reported cases of patients carrying the same mutation, we demonstrate the complexity of the disease and the necessity of correctly correlating the phenotype with the genotype. Here, we present a minireview and a case report of EIEE13 involving the rare p.Arg1872Gln mutation in the SCN8A gene. We used targeted next-generation sequencing to examine a six-year-old girl with complex partial seizures from the left temporal lobe since 4 months of age. The condition was difficult to control with medication and the seizures evolved to generalised tonic-clonic seizures after the age of 3 years. Neurodevelopment in the child became severely delayed although seizures were as rare as 1 in every 5-10 months. А heterozygous missense mutation in the SCN8A gene (NM_014191.3:c.5616G > A, NP_055006.1:p.Arg1872Gln) was found. The variant was validated by Sanger sequencing. We suggest that this SCN8A mutation has a primary neurodegenerative effect leading to brain atrophy and intellectual disability (with or without autism) that is partially independent of its epileptogenic effect. Our results demonstrate that the application of large panels with clinically-associated genes is essential for identifying rare mutations in individuals with disorders of unknown etiology. [ABSTRACT FROM AUTHOR]

An ever larger portion of the world population survives into advanced old age, and that has been a steady trend for the last century. Despite some substantial advances in our understanding of the genomic basis of ageing in recent years, healthy ageing remains an increasingly important social task. Initially established in model organisms, many human orthologue genes and pathways associated with longevity have been identified. Ageing is a result from the declining ability of the human organism to maintain homeostatic balance and to regenerate damaged cells and tissues, and is the main risk factor for the prevalent diseases in developed countries. It could be imagined that the genome of very old individuals is purged of disease-causing variants, but recent studies have demonstrated that long-lived individuals carry the same number of disease alleles as young controls. Longevity may however also be explained by the presence of protective genetic factors against age-related phenotypes and diseases, and there is a pertinent need for these to be identified. Centenarians are the extreme phenotype of human longevity and their genomes undoubtedly contain clues about genes and pathways that are involved in longevity. Understanding the genomic basis of ageing, together with knowledge of population ecology and insights from evolutionary biology, will shed light on the biological mechanisms underlying human longevity and hence on the potential of extending healthy human life span. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVD) comprise a broad range of disorders of the heart and blood vessels. In this study, we used next-generation sequencing with a panel that includes 174 genes connected to CVD in order to investigate the possible genetic causes that underline some clinical phenotypes and their severity. Two patients were found with double heterozygosity, each carrying one new variant. One patient with supravalvular aortic stenosis has novel ELN: c.890-1G>A and a known variant SCN5A: p.Gly9Val in a heterozygous state, whereas another patient with hypertrophic cardiomyopathy has a heterozygous novel CACNA1C: p.Arg514Gly and a known SCN5A: p.Arg800His variant. This method proved to be useful in determining the mutation status in correlation with the severity of the clinical phenotype and can further clarify cases where the clinical status could not be explained only by single gene mutation detected by standard methods. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the most common malignant tumour of the endocrine system. One of the most frequent types of thyroid malignancy is papillary carcinoma. In our study, we performed next generation sequencing (NGS) using a cancer panel (Illumina; Illumina, San Diego, USA) to screen for pharmacogenetic susceptibility variants in blood samples of 10 patients with papillary thyroid cancer (PTC). We report variants rs1042522 (TP53), rs2228001 (XPC), rs2227983 (EGFR), rs13181 (ERCC2), rs17655 (ERCC5) and rs1799939 (RET), which were detected in the analyzed patients either in homozygous and/or heterozygous state previously known to be connected with pharmacogenetic sensitivity to certain drugs in oncology. The results showed the TruSight Cancer Panel to be a useful clinical tool for determination of oncotherapy-associated pharmacogenetic variants in the blood of patients. [ABSTRACT FROM AUTHOR]

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease associated with urothelial cancer, which affects people living in the alluvial plains along the tributaries of the Danube River. Challenges of studying BEN using the epidemiological method are multiple. The natural history from exposure to occurrence of the disease may take many years. The early stages of BEN are not easily detectable clinically, as the disease is asymptomatic until a significant decline in function occurs, and even then symptoms are usually non-specific. The natural history of BEN is complex, possibly with multiple risk factors operating both at the stage of initiation of renal damage and in its progression. In BEN, genetic susceptibility is due to multiple genes of small effects, gene-gene interactions, and gene-environment interactions of complex nature that are difficult to assess with current study designs. BEN is now kidney disease of the old people, and many risk factors for disease such as smoking, alcohol consumption, obesity, and diabetes could contribute to the kidney damage. Evidence is presented that environmental rather than genetic factors play a decisive role in the etiopathogenesis of BEN. Aristolochic acid, described as a culprit of BEN in 1959, is confirmed in 2007 by the molecular biology methods. Mycotoxins and polycyclic aromatic hydrocarbons, leached from lignites and found in the vicinity of endemic settlements, deserve further investigation. Despite advances in understanding the epidemiology of BEN, more research is needed on the patterns of BEN over time and between places, and on identifying the contributions of modifiable risk factors in initiating and hastening progression of BEN in order to improve the scope for preventing BEN. Primary prevention is still at the beginning. Knowledge accumulated in the fifty years of BEN research and new data about prevention and treatment of chronic kidney disease reveal several effective methods in secondary and tertiary prevention of BEN. Genetic epidemiology could establish the relative size of the genetic effect in relation to other sources of variation in disease risk (i.e., environmental effects such as intrauterine environment, physical and chemical effects, as well as behavioral and social aspects). Public health authorities in the several countries having aristolochic acid nephropathy should take immediate measures for reducing dietary exposure of residents to Aristolochia. [ABSTRACT FROM AUTHOR]

Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression to terminal renal failure. Diagnostic criteria for BEN have been described more than 40 years ago. Research groups on BEN use one of at least three described lists of criteria. Comparison of studies using such criteria is difficult, and a recent meeting of investigators (Zagreb, October 2006) has suggested that unified criteria have to be elaborated. In this paper, an International Panel of BEN Investigators agreed on criteria appropriate to epidemiologic studies and clinical investigations of BEN. A screening procedure of BEN in endemic settlements is proposed. [ABSTRACT FROM AUTHOR]