Sadašnjost i budućnost prenatalne dijagnostike u Sloveniji

Prenatal genetic testing is under the remit of the National Health Service in Slovenia and has been included in clinical routine since the 1980s. Traditionally, prenatal services have consisted of karyotyping and rapid fetal aneuploidy screening to detect chromosome abnormalities, whereas targeted mutation testing was used for single gene disorders. Development of array comparative genomic hybridization and next generation sequencing allows for genome analysis at better resolution in a single experiment. While technological advances in medicine continue to evolve, increasing diagnostic accuracy and broadening the spectrum of indications, all these innovations require more investment along with more equipment and higher staffi ng rations trained to use it, placing burden upon healthcare funding and expenditure. This prompts us to consider how to implement new techniques into the existing services in order to update genetic services for the 21st century. Our aim is to develop a new approach to prenatal genetic services, which would maximize diagnostic yield at an acceptable cost.Prenatalno genetičko testiranje u nadležnosti je Državne zdravstvene djelatnosti u Sloveniji i uključeno je u kliničku praksu od 1980.-ih godina. Prenatalne usluge tradicionalno obuhvaćaju kariotipiziranje i brz probir na fetalne aneuploidije kako bi se otkrile kromosomne anomalije, dok se za poremećaje jednog gena provodilo ciljano testiranje na mutacije . Razvoj komparativne genomske hibridizacije na mikropostroju i sekvenciranje sljedeće generacije omogućava analizu genoma uz bolju rezoluciju u jednom testu. Dok se tehnološki napredak u medicini nastavlja poboljšavajući tako dijagnostičku točnost i šireći lepezu indikacija, ove inovacije zahtijevaju sve veća ulaganja i sve više opreme te dodatno osposobljeno osoblje koje će raditi s tom opremom, što opterećuje zdravstvene fondove i povećava troškove. To nas potiče da razmotrimo kako uklopiti nove tehnike u postojeću službu kako bismo genetičke usluge prilagodili potrebama 21. stoljeća. Cilj nam je razviti nov pristup prenatalnoj genetici kojim će se postići najučinkovitiji rezultati uz prihvatljive troškove

Deletion/Deletion Genotype of Angiotensin-I Converting Enzyme Gene is not Associated with Coronary Artery Disease in Caucasians with Type 2 Diabetes

In this study we analyzed the contribution of genetic variability of the insertion/deletion (I/D) polymorphism of the angiotensin-I converting enzyme (ACE) gene to the predisposition for coronary artery disease (CAD) in a group of patients with type 2 diabetes. The I/D ACE gene polymorphism was tested in 366 Caucasians with type 2 diabetes: 148 cases with CAD and 218 subjects with no history of CAD. We failed to demonstrate that the ACE DD genotype was a risk factor for CAD in Caucasians with type 2 diabetes (OR 2.0, 95 % CI 0.9–4.7; p=0.1). In conclusion, we provide evidence that the ACE deletion/deletion genotype is not a risk factor for CAD in Caucasians with type 2 diabetes

The ScaI Gene Polymorphism of the Atrial Natriuretic Factor and Essential Arterial Hypertension in Childhood

In order to investigate the contribution of the atrial natriuretic factor (ANF) gene in pathogenesis of essential arterial hypertension (EAH), we analyzed the ScaI gene polymorphism of the ANF gene in a group of children with EAH. Fifty-eight children, aged 8–19 years, with the diagnosis of EAH were included in the association study and were compared to 57 subjects with normal blood pressure (the control group). Arterial hypertension was defined as systolic/diastolic blood pressure higher than the 95th age-gender--height percentile of the adopted reference values. We failed to demonstrate an association between the ScaI ANF gene polymorphism and EAH in childhood (OR=2; 95% CI 0.9–4.2; p=0.07), however, we provided evidence of an interaction between the ScaI ANF gene polymorphism and obesity defined as BMI over the 85th percentile (OR=13.1; 95% CI 1.6–106; p<0.001)

Frequency of HFE Gene Mutations C282Y and H63D in Bosnia and Herzegovina

Genetic epidemiology studies of hereditary hemochromatosis (HHC) have shown a high prevalence of the C282Y mutation in individuals of the North Western European origin, whereas lower prevalence of HFE gene mutations was detected in the populations from southern European countries. However, no HFE mutation prevalence data have been provided for the population of Bosnia-Herzegovina so far. Therefore, the aim of this study was to determine the frequency of the C282Y and H63D HFE gene mutations in the population of Bosnia-Herzegovina. Among 200 analysed subjects 8 (4%) were C282Y heterozygotes; no C282Y homozygotes were found. The frequency of the H63D allele was 11.5%. There were 33 (16.5%) heterozygotes and 6 (3%) homozygotes for the H63D mutation. One (0.5%) compound heterozygote C282Y/H63D was identified. The observed C282Y and H63D allele frequency was 2.25% (95% confidence interval: 1.2–4.2) and 11.5% (95% confidence interval: 8.7–14.9), respectively. The prevalence of the C282Y and H63D mutations was estimated in Bosnia-Herzegovina, which fit well in the European northwest-to-southeast gradient of the C282Y mutation distribution. In addition, these results have an important implication for clinical evaluation of HHC in Bosnia- Herzegovina

The –429 T/C and –374 T/A Gene Polymorphisms of the Receptor of Advanced Glycation End Products Gene (RAGE) are not Risk Factors for Coronary Artery Disease in Slovene Population With Type 2 Diabetes

Receptor for advanced glycation end products (RAGE) plays a role in atherosclerosis in diabetics. There are two functional polymorphisms in the promoter of the RAGE gene (–429T/C and –374T/A). The aim of this study was to look for a relationship between the –429T/C and the –374T/A gene polymorphisms of the RAGE gene and the development of coronary artery disease (CAD) in the Slovene population with type 2 diabetes of duration longer than 10 years. One hundred and sixty-eight subjects with diabetes and CAD were compared to 241 diabetic subjects without CAD. The –429T/C and the –374T/A RAGE genotype distributions in patients with CAD (–429T/C: CC: 3%, TC: 31%, TT: 66.0%; 374T/A: AA: 7.7%, TA: 48.2%, TT: 44.1%) were not significantly different from those in patients without CAD (–429 T/C: CC: 1.7%, TC: 26.1%, TT: 72.2%; –374T/A: AA: 11.2%, TA: 43.2%, TT: 45.6%). Our study failed to demonstrate an association between either the –429T/C or the –374T/A gene polymorphism of the RAGE gene and CAD in the Slovene population with type 2 diabetes of duration longer than 10 years

The –429 T/C and –374 T/A Gene Polymorphisms of the Receptor of Advanced Glycation End Products Gene (RAGE) are not Risk Factors for Coronary Artery Disease in Slovene Population With Type 2 Diabetes

Receptor for advanced glycation end products (RAGE) plays a role in atherosclerosis in diabetics. There are two functional polymorphisms in the promoter of the RAGE gene (–429T/C and –374T/A). The aim of this study was to look for a relationship between the –429T/C and the –374T/A gene polymorphisms of the RAGE gene and the development of coronary artery disease (CAD) in the Slovene population with type 2 diabetes of duration longer than 10 years. One hundred and sixty-eight subjects with diabetes and CAD were compared to 241 diabetic subjects without CAD. The –429T/C and the –374T/A RAGE genotype distributions in patients with CAD (–429T/C: CC: 3%, TC: 31%, TT: 66.0%; 374T/A: AA: 7.7%, TA: 48.2%, TT: 44.1%) were not significantly different from those in patients without CAD (–429 T/C: CC: 1.7%, TC: 26.1%, TT: 72.2%; –374T/A: AA: 11.2%, TA: 43.2%, TT: 45.6%). Our study failed to demonstrate an association between either the –429T/C or the –374T/A gene polymorphism of the RAGE gene and CAD in the Slovene population with type 2 diabetes of duration longer than 10 years

Insertion/Deletion Polymorphism of Angiotensin-Converting Enzyme Gene – Risk Factor for Coronary Artery Disease in the Tuzla Region Population (Bosnia and Herzegovina

Angiotensin II is the major effector molecule of renin-angiotensin system; its production can be conveniently interrupted by angiotensin-converting enzyme (ACE). Typical plasma levels of ACE accompany the I/D polymorphism; however, a controversy exists as to whether the DD genotype of the ACE polymorphism affects the risk for the development of coronary artery disease (CAD) and to what extent the ACE polymorphism is associated with CAD in different populations. We compared the I/D polymorphism in 212 CAD patients younger than 50 years with 165 healthy control individuals. They were all from the Tuzla region in Bosnia and Herzegovina. Patients with CAD had a higher prevalence of the DD genotype (36.3%) than controls (25.6%). The odds ratio for the ACE DD genotype in CAD patients was 1.7 (95% confidence interval 1.0–2.7; p<0.05).We may conclude that the D/D genotype of the ACE gene polymorphism is associated with an increased risk for CAD in the Bosnian population

Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss

<div><p>Hereditary hearing loss (HL) is a common sensory disorder, with an incidence of 1–2 per 1000 newborns, and has a genetic etiology in over 50% of cases. It occurs either as part of a syndrome or in isolation and is genetically very heterogeneous which poses a challenge for clinical and molecular diagnosis. We used exome sequencing to seek a genetic cause in a group of 56 subjects (49 probands) with HL: 32 with non-syndromic non-<i>GJB2</i> HL and 17 with syndromic HL. Following clinical examination and clinical exome sequencing, an etiological diagnosis was established in 15 probands (15/49; 30%); eight (8/17;47%) from the syndromic group and seven (7/32; 21%) from the non-syndromic non-<i>GJB2</i> subgroup. Fourteen different (half of them novel) non-<i>GJB2</i> variants causing HL were found in 10 genes (<i>CHD7</i>, <i>HDAC8</i>, <i>MITF</i>, <i>NEFL</i>, <i>OTOF</i>, <i>SF3B4</i>, <i>SLC26A4</i>, <i>TECTA</i>, <i>TMPRSS3</i>, <i>USH2A</i>) among 13 probands, confirming the genetic heterogeneity of hereditary HL. Different genetic causes for HL were found in a single family while three probands with apparent syndromic HL were found to have HL as a separate clinical feature, distinct from the complex phenotype. Clinical exome sequencing proved to be an effective tool used to comprehensively address the genetic heterogeneity of HL, to detect clinically unrecognized HL syndromes, and to decipher complex phenotypes in which HL is a separate feature and not part of a syndrome.</p></div

Clinical characteristics of HL probands with rare variants.

<p>Clinical characteristics of HL probands with rare variants.</p

Disease causing variants and variants of uncertain significance in HL probands.

<p>Disease causing variants and variants of uncertain significance in HL probands.</p