Re-evaluation of Genetic Variants in Parkinson's Disease Using Targeted Panel and Next-Generation Sequencing.

Parkinson's disease (PD) is a complex disorder with a significant genetic component. Genetic variations associated with PD play a crucial role in the disease's inheritance and prognosis. Currently, 31 genes have been linked to PD in the OMIM database, and the number of genes and genetic variations identified is steadily increasing. To establish a robust correlation between phenotype and genotype, it is essential to compare research findings with existing literature. In this study, we aimed to identify genetic variants associated with PD using a targeted gene panel with next-generation sequencing (NGS) technology. Our objective was also to explore the idea of re-analyzing genetic variants of unknown significance (VUS). We screened 18 genes known to be related to PD using NGS in 43 patients who visited our outpatient clinic between 2018-2019. After 12-24 months, we re-evaluated the detected variants. We found 14 different heterozygous variants classified as pathogenic, likely pathogenic, or VUS in 14 individuals from nonconsanguineous families. We re-evaluated 15 variants and found changes in their interpretation. Targeted gene panel analysis with NGS can help identify genetic variants associated with PD with confidence. Re-analyzing certain variants at specific time intervals can be especially beneficial in selected situations. Our study aims to expand the clinical and genetic understanding of PD and emphasizes the importance of re-analysis.

Clinical and molecular evaluation of MEFV gene variants in the Turkish population: a study by the National Genetics Consortium.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease.

The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

A New Mutation, Hb A2-Canakkale [δ10(A7)Ala→Val; HBD: c.32C>T], and Other Well-Known δ Variants Identified in a Selected Cohort with Low Hb A2 Levels.

Hemoglobinopathies are the most common single-gene disorders, and ß-thalassemia (ß-thal) imposes a tremendous health burden on Turkey. Thus, premarital carrier screening is obligatory in Turkey, as it is in some other countries. As a result of this mandatory procedure, at routine clinical checkups, many individuals who had undergone premarital screening but did not have any clinical symptoms and/or hematological findings, have compulsorily been required to undergo further evaluation due to abnormal levels of hemoglobin (Hb) fractions (Hb A, Hb A2 and Hb F). Many consequences, such as mutations in unrelated gene(s) or someone's nutritional status, have been reported to affect the Hb fractions levels. In the present study, we aimed to determine whether HBD has a molecular causative role in patients with low Hb A2 levels (below 1.8%). The study was conducted with 20 individuals with low Hb A2 levels who had applied to our outpatient clinic. All DNA samples were analyzed for the HBD gene. Nineteen of the 20 subjects were diagnosed to carry a mutation with one of four different δ-globin variants. Three of them had been described previously [Hb A2-Yialousa (HBD: c.82G>T), Hb A2-Bornova (HBD: c.350G>C) and Hb A2-Yokoshima (HBD: c.77G>A)]. The novel [δ10(A7)Ala→Val, HBD: c.32C>T] mutation was defined as a new δ variant and reported to the HbVar database as Hb A2-Canakkale. In conclusion, the molecular characterization of Hb A2 low levels has been suggested to be significant for a definite diagnosis and counseling.

Copy number variations in patients with idiopathic recurrent pregnancy loss: an arrayCGH approach.

BACKGROUND: It is not always possible to determine the causative basis of pregnancy losses and even today it has been reported that 50% of cases with recurrent pregnancy loss (RPL) have no reason to be detected. In our study, it is aimed to reveal the copy number variations (CNVs) of the genes which presumably have a potential effect in individuals with RPL and contribute to subsequent functional studies in the follow-up. METHODS: We retrospectively evaluated the array-comparative genomic hybridization (aCGH) data of cytogenetically 64 normal individuals (21 couples, 11 unrelated women, and 11 unrelated men) who had applied to our outpatient clinic from January 2016 to December 2017, for the history of idiopathic two or more RPL. RESULTS: A total of 83 CNVs were detected in 56 different chromosomal regions [36% (20/56) is deletion and 64% (36/56) is duplication] in 40/64 (62.5%) of the cases. Two detected deleterious CNVs encompassing 1p36.22-p36.21 and 10q11.22 chromosomal locus have been reported as pathogenic according to the Database of Genomic Variants (DGV). DISCUSSION: CNVs that may play a role in the genetic etiology of idiopathic RPL were revealed in our study and potential chromosomal loci were introduced to the literature for further analysis. The detection of CNVs and their association with reproduction such as RPL, infertility, and even other diseases will allow us to have more information about the clinical consequences and will make it possible to provide more accurate and comprehensive genetic counseling.

The prevelance of human papillomavirus (HPV) genotypes detected by PCR in women with normal and abnormal cervico-vaginal cytology.

OBJECTIVES: Cervical cancer is the second most common type of cancer for women worldwide with a great proportion proved to be related to human papillomavirus (HPV) infection. As infection with HPV is the strongest risk factor for cervical neoplasia, detection of HPV genotypes in cervical and vaginal specimens of women with normal and abnormal cytology seems to be of paramount importance in cervical cancer screening. The objective of the study is to evaluate the prevalence and HPV genotypes among women with normal or abnormal Pap smear tests. MATERIAL AND METHODS: This retrospective study was conducted in a tertiary care university hospital in western Turkey. A total of 201 patients in whom both HPV typing and Pap test was performed between 2012 and 2016 in our obstetrics and gynecology department were enrolled in this study. Clinical and laboratory data were obtained for all participants. Cervical smears of the patients were classified by the Bethesda system and HPV analyses were done using the polymerase chain reaction (PCR) method. RESULTS: This study included 201 women, 72 of whom had normal and 129 of whom had abnormal Pap smear results. HPV DNA was detected in 91 (45.2%) of the 201 investigated women. Out of 72 patients with normal cervico-vaginal cytology, HPV positivity was detected in 35 (49%) patients, whereas 33 (35%) patients out of 94 with ASCUS , 18 (62%) patients out of 29 with LSIL and 5 (83%) patients out of 6 with HSIL had HPV positivity. Out of 35 HPV positive women that had normal pap test results, 25 (75%) were found to have high risk HPV (HR-HPV) genotypes. In women with ASCUS, LSIL and HSIL, HR-HPV genotype rates were found to be 94%, 89% and 100% respectively. The most common identified HPV types were HPV58, HPV16, HPV31, HPV33, HPV11 and HPV35. CONCLUSIONS: The frequency of HPV infection was found to be higher in our study compared to previous reports. Moreover, although HR-HPV genotypes were also detected in patients with normal cervical cytology, a majority of patients with HR-HPV genotypes were associated with abnormal cervical smear cytology including high rates of atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion.

Bcii--RFLP profiles for serum amiloid A1 and mutated MEFV gene prevalence in chronic renal failure patients requiring long-term hemodialysis.

BACKGROUND AND AIM: There is an increased mortality risk in long-term hemodialysis patients of renal failure due to the chronic inflammation. The relationship between the chronic renal failure (CRF) and the role of familial genetic markers remains incompletely understood. In the current study, it was aimed to find out the prevalence of common MEFV gene mutations and BcII polymorphism in serum amyloid A1 (SAA1) gene in chronic renal patients (CRF) who require long-term hemodialysis. METHOD: Current cohort includes 242 CRF patients and 245 healthy individuals from the same population. Total genomic DNA was isolated from peripheral blood-EDTA samples and genotyping of target MEFV gene was carried out by reverse hybridization Strip Assay and real-time techniques. The SAA1 gene was genotyped by the BclI-RFLP method. RESULTS: Increased mutated MEFV genotypes were found in current CRF patients when compared with the control group from the same ethnicity and the difference was statistically significant (Table 2) (OR: 4.9401, 95% CI: 3.0694-7.9509), p<0.0001. The most frequent point mutations were M694V and E148Q. The mutated T allel frequency in the SAA1 gene was also different when compared with the healthy controls and the difference was found to be statistically significant (χ2: 13.18; p=0.000). CONCLUSIONS: The current results indicate the germ-line mutations in both genetic biomarkers (MEFV and SAA1 genes) that are related to inflammation and amyloidosis processes may play a crucial role in CRF pathogenesis due to the long-term chronic inflammation.

Intercellular adhesion molecule-1 K469E and angiotensinogen T207M polymorphisms in coronary slow flow.

OBJECTIVE: To investigate intercellular adhesion molecule-1 (ICAM1) and angiotensinogen (AGT) gene polymorphisms, as related to atherosclerosis and endothelial dysfunction, in coronary slow flow (CSF). SUBJECTS AND METHODS: The participants in this study were 48 patients with CSF and 67 patients with normal coronary flow as controls. The K469E polymorphism of ICAM1 (rs5498) and the T207M polymorphism of AGT (rs4762) were determined using the polymerase chain reaction amplification method. RESULTS: Baseline demographic parameters were similar in both groups. The mean thrombolysis in myocardial infarction frame count was significantly higher in patients with CSF (23.8 ± 5.1) compared to the controls (13.3 ± 2.6, p < 0.001). A significant association was found between the ICAM1 K allele and CSF (OR: 1.96, 95% CI: 1.15-3.35, p = 0.013). There was no difference in the frequency of AGT T207M genotypes in the patients with CSF and the control subjects. CONCLUSION: This study showed that K469E polymorphisms of ICAM1 that play a role in atherosclerotic pathogenesis are related to CSF.

Combined point mutations in codon 12 and 13 of KRAS oncogene in prostate carcinomas.

Prostate cancer is a common malignancy that develops by structural mutation(s) and/or other genetic alterations in specific genes.The G to T transversions in codon 12 and C to T transitions in codon 13 of KRAS proto-oncogene are predominant point mutations that occur in about 20% of different cancers in human. In the current study it was aimed to investigate the prevalence and predictive significance of KRAS mutations in patients with prostate carcinomas. In a total of 30 fresh tumoural tissue specimens were investigated in patients with prostate carcinoma. All tumoural specimens were histo-pathologically diagnosed and genotyped for codon 12, 13 KRAS point mutations by reverse hybridisation and direct sequencing methods. KRAS mutations were found in 12 (40%) samples with 29 samples deriving from adenocarcinomas and 1 sample was small cell prostate carcinoma. In 1 (3.44%) sample codon 12 was found to be mutated and in 2 (6.8%) samples codon 13 and in 9 (31%) samples combined codon 12 and 13 were found to be mutated particularly in higher grade of tumoural tissues. Our study, based on representative collection of human prostate tumours, indicates that combined mutations in codons 12 and 13 KRAS are relatively infrequent and most commonly occur in prostate carcinomas.

The prevalence of VKORC1 1639 G>A and CYP2C9*2*3 genotypes in patients that requiring anticoagulant therapy in Turkish population.

The aim was to investigate the prevalence of VKORC1 and CYP2C9 genotypes in patients requiring anticoagulant therapy in two different region's populations of Turkey. The recent cohort included 292 patients that needed anticoagulant therapy, and who had a history of deep vein thrombosis and/or pulmonary artery thromboembolism. Genomic DNA was isolated from peripheral blood samples and the StripAssay reverse hybridization or Real Time PCR technique was used for genotype analysis. Genotypes for CYP2C9 were detected as follows: 165 (56.5 %) for CYP2C9*1/*1, 67 (23.0 %) for CYP2C9*1/*2, 25 (8.6 %) for CYP2C9*1/*3, 9 (3.0 %) for CYP2C9*2/*2, 21 (7.2 %) for CYP2C9*2/*3, 5(1.7 %) for CYP2C9*3/*3 for CYP2C9 and the allele frequencies were: 0.723 for allele*1, 0.182 for allele*2 and 0.095 for allele*3 respectively. Genotypes for VKORC1 were detected as follows: 64 (21.9 %) for GG, 220 (75.4 %) for GA and 8 (2.7 %) for AA alleles. The G allele frequency was detected as 0.596, and the A allele frequency was 0.404. The VKORC1 1639 G>A and CYP2C9 mutation prevalence and allele frequency of the current results from two different populations (Sivas and Canakkale) showed similarly very variable profiles when compared to the other results from the Turkish population.

A New Case of Rare Microdeletion 10q22.3q23 along with Mosaic Klinefelter Syndrome Associated with Facial Dysmorphic Finding, Atrial Ventricular Septal Defect, and Motor Retardation.

The chromosome 10q22.3q23.2 deletion syndrome is characterized by craniofacial dysmorphic features, developmental delay, congenital heart defect, and hand/foot abnormalities. In this study, we report a patient carrying a microdeletion of 7.5 Mb at 10q22.3q23.2 and in addition a mosaicism mos 47,XXY[47]/46,XY[23]. This male patient was 3 years and 3 months years old at the time of genetic evaluation. Atrial ventricular septal defect (AVSD), mild hypotonia, torticollis, and left-sided club foot were noticed after birth. The boy had surgical correction of the AVSD and the club foot. His dysmorphic features were frontal bossing, overfolded ear helix, hypertelorism, epicanthal folds, broad base of nose, flat nasal bridge, full cheeks, thick lips, micrognathia, and joint hyperextensibility. His speech/language development was delayed. Klinefelter syndrome is one of the most common congenital chromosomal abnormalities, but usually it is detected in puberty or in adulthood when reproductive failure occurs. Deletions in the 10q22.3q23.2 region are rare, and previously only a few numbers of cases were described with this microdeletion, but none of them together with Klinefelter syndrome and it could be associated with our case clinical features. The new case described will improve understanding the phenotype associated with 10q22.3q23.2 microdeletions. By presenting this case, we aimed to improve the understanding of the phenotype caused by the rare 10q22.3q23.2 deletion and to show the rare coexistence of this deletion with Klinefelter syndrome.

The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk.

This study aimed to determine the relation between methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism and lung cancer risk and the frequency of this polymorphism. The study involved 64 lung cancer patients (the study group) with definitive diagnosis and 61 noncancerous subjects (the control group). MTHFR C677T and A1298C mutation analysis was made using DNA isolated from peripheric blood and multiplex PCR and reverse hybridization strip test. Eighty-four percent of the patients were male. The age, gender, and history of alcohol use of the patients and control group were statistically similar. While MTHFR 677T and 677C allele frequency was 0.33 and 0.67 in the patients respectively, it was 0.29 and 0.71 in the control group. The frequencies of MTHFR 1298C and 1298A were 0.33 and 0.67 in the patients, and it was 0.31 and 0.69 in the control group respectively. When MTHFR 677TT and 677CT genotypes were compared with 677CC genotype, lung cancer risk was 2.4 times higher in the 677TT genotype. When MTHFR 1298AC and 1298CC genotypes were compared with 1298AA genotype, lung cancer risk was 1.5 times higher in 1298CC genotype. According to the results, allele frequency of homozygote T and C was high in lung cancer patients. It was 3.05 and 1.29 times higher in smokers than in non-smokers, and 3.05 and 1.64 times higher in males than in females; 3.0 and 2.44 times higher in those with non-small cell lung cancer than in those with small-cell lung cancer.

Prevalence of known mutations in the MEFV gene in a population screening with high rate of carriers.

The Familial Mediterranean Fever (FMF) shows an autosomal recessive pattern of inheritance and affects certain ethnic groups. Disease is caused by mutations in MEFV gene and more than 180 mutations have been defined in affected individuals. Current study aimed to determine the frequency-type of the mutations for MEFV gene in Sivas-middle Anatolian city. The cohort was composed of 3340 patients. MEFV gene mutations were studied by multiplex PCR based reverse hybridization stripAssay method. Patients' clinical features were; family history: 68%, erysipelas-like erythema: 17.6%, fever: 89.9%, abdominal pain: 84.2%, peritonitis: 90.2%, arthritis: 33%, pleuritis: 14.2%, parental consanguinity: 21.2%. Current results revealed that M694V is the most frequent mutation (43.12%), followed by E148Q (20.18), M680I(G/C) (15.00%) and V726A (11.32%). The study population has a high rate of carriers and the E148Q mutation frequency was found to be highest when compared to the other regions of Turkey and other Mediterranean groups.

The presence of PAI-1 4G/5G and ACE DD genotypes increases the risk of early-stage AVF thrombosis in hemodialysis patients.

BACKGROUND: In this study, we investigated the relationship between early arteriovenous fistula (AVF) thrombosis with angiotensin-converting enzyme (ACE) gene and thrombophilic factor gene polymorphisms. METHODS: Thirty-five patients who suffered from three or more fistula thrombosis episodes in the early period after AVF operation and 33 control patients with no history of thrombosis for at least 3 years were enrolled in this study. RESULTS: Factor V G1691A Leiden, factor V H1299R (R2), prothrombin G20210A, factor XIIIV34L, ß-fibrinogen-455 G-A, glycoprotein IIIa L33P human platelet antigens (HPA-1), methylenetetrahydrofolate reductase C677T, and methylenetetrahydrofolate reductase A1298C gene polymorphisms were similar in both groups (p > 0.05). Plasminogen activator inhibitor 1 (PAI-1) 4G/5G genotype in the study group and 4G/4G genotype in the control group were significantly higher (p = 0.014). No significant difference was detected in terms of the 5G/5G genotype. With regard to the ACE gene polymorphism, the control group showed more ID genotype (19/33, 57.6%), whereas the study group showed more DD genotype (17/35, 48.6%). II genotype was similar in both groups (x(2) = 7.40, p = 0.025). The rate of ACE inhibitor-angiotensin II receptor blockers use was 5/35 in the study group (14.3%) and 5/33 in the control group (15.2%). Individuals with PAI-1 4G/5G genotype showed 5.03 times more risk of thrombosis when compared with 4G/4G and 5G/5G genotypes [p = 0.008, OR = 5.03, 95% confidence interval (1.44:17.64)]. Individuals with ACE DD genotype showed 4.25 times more risk of thrombosis when compared with II and ID [p = 0.008, OR = 4.25, 95% confidence interval (1.404:12.83)]. CONCLUSION: PAI-1 4G/5G and ACE DD genotypes are associated with increased risk for early AVF thrombosis.

Association between ABCB1 (MDR1) gene 3435 C>T polymorphism and colchicine unresponsiveness of FMF patients.

The multidrug resistance gene-1 (MDR1, adenosine triphosphate-binding cassette transporter: ABCB1, P-glycoprotein) encodes membrane proteins that play a crucial role in protecting cells from xenobiotics, chemicals, and drugs. The TT genotype of 3435 codon in exon 26 of MDR1 gene causes overexpression of gene activity and effluxes many chemically diverse compounds across the plasma membrane. We studied the association between C3435T polymorphisms (single nucleotide polymorphism) of MDR1 gene and colchicine-resistant familial Mediterranean fever (FMF) patients. Total genomic DNA samples from 52 FMF patients of colchicine unresponsiveness were used for FMF (MEFV) and MDR1 genes profile analyses. Target genes were genotyped by multiplex PCR-based reverse-hybridization Strip Assay method. The preliminary current results showed increased T allele frequency (0.596) in colchicine unresponsiveness of FMF patients. The distributions of the CC, CT, and TT genotypes in colchicine nonresponder FMF patients were 17%, 46%, and 37%, respectively. Our results indicate that C3435T polymorphism in exon 26 of MDR1 gene is associated with colchicine resistance in nonresponder FMF patients during the common therapy protocol.

In vivo evaluation of the genotoxic effects of gonadotropins on rat reticulocytes.

BACKGROUND: Gonadotropins, as ovulation-inducing drugs, have been used widely to treat infertility. An epidemiologic correlation between infertility therapy and ovarian cancer development has been reported. However, the effect of gonadotropins in the formation of reproductive tract cancers is controversial. OBJECTIVE: The aim of the study was to determine the in vivo genotoxic effects of gonadotropins on rat reticulocytes. METHODS: In this prospective, randomized, controlled study, rats were randomly assigned to 1 of 5 groups. The calculated rat doses of 0.65 human menopausal gonadotropin (hMG), 0.95 hMG, 0.65 follitropin beta (FB), 0.95 FB, or normal saline (control group) were injected, respectively. These calculated rat doses (U/g) are based on average human gonadotropin doses of 150 and 225 IU/d for a 70-kg woman given in 2-mL saline (the control group received 2 mL of saline). Injections were administered once per day for 5 days, followed by 5 days of rest. Each treatment was repeated for 6 estrus cycles in the rats for a total of 12 estrus cycles. Six months after the last day of the 12(th) cycle, the rats were euthanized. Bone marrow tissues were removed, and pluripotent reticulocyte cells with micronuclei, nuclear buds, and binuclear abnormalities were analyzed using an in situ micronuclei assay under light microscopy. The proportion of micronucleated cells, cells with anaphase bridge, nuclear buds, and other nuclear abnormalities were measured. RESULTS: The number of cells with nuclear buds and binuclear abnormalities in the hMG 225 and FB 225 groups was significantly higher (P < 0.05) than that from the hMG 150, FB 150, and control groups in the cytogenetic analysis of bone marrow stem cells. An increased rate of genotoxicity in all gonadotropin groups versus that of placebo was found. CONCLUSION: In rats, the micronucleus genotoxicity assay suggests a dose-dependent gonadotropin effect on genomic instability in bone marrow stem cells in vivo.

The high frequency of chromosomal copy number variations and candidate genes in epilepsy patients.

OBJECTIVE: Epilepsy is a chronic brain disease and is estimated to affect more than 50 million people worldwide.Epilepsy is a polygenic and multifactorial disease.Genetic causes play a major role in 40-60 % of all epilepsies.Copy number variations(CNVs) have been reported in approximately 5-12 % of patients with different types of epilepsy.Here we aimed to determine the diagnostic yield of the aCGH in epilepsy and to reveal new candidate genes and CNVs by analyzing aCGH data retrospectively. METHODS: The clinical data of 80 patients with the diagnosis of epilepsy were examined retrospectively and the raw data of aCGH of these patients were reanalyzed in the light of current literature. RESULTS: Pathogenic/likely pathogenic CNVs were detected in 14 of 80 patients and 12 of these CNVs (15 %) were associated with epilepsy phenotype. In addition, 18 CNVs in 16 different chromosomal loci that were evaluated as the variant of unknown clinical significance(VOUS). In four cases (5%), CNVs associated with epilepsy were less than 100 kb and these accounted for 13.3 % of all epilepsy associated CNVs. CONCLUSION: The diagnostic yield of aCGH in epilepsy patients was found to be higher than most studies in the literature. MACROD2,ADGRB3(BAI3),SOX8,HIP1,PARK2 and TAFA2 genes were evaluated as potential epilepsy-related genes and NEDD9,RASAL2 and TNR genes thought to be the candidate genes for epilepsy. Our study showed that the diagnostic efficiency of aCGH in epilepsy is high and with more comprehensive studies, it will contribute to the elucidation of genes involved in genetic etiology in epilepsy patients.

Prognostic Prediction of BRCA Mutations by 18F-FDG PET/CT SUVmax in Breast Cancer

Objectives: This study aimed to investigate the prognostic prediction of germline BRCA1 and BRCA2 mutations by comparing the maximum standardized uptake value (SUVmax) obtained from 18fluoride-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), which is considered a prognostic factor in breast cancer (BC). Methods: Retrospective interdisciplinary laboratory results of 92 patients with BC who had germline BRCA1 or BRCA2 mutation profiles and underwent 18F-FDG PET/CT were compared. Genotyping was made by next-generation sequencing, and PET/CT scans were re-evaluated. The histopathological data, genetic results, and clinical demographics of all patients were recorded. Patients were divided into two groups in accordance with the presence of germline BRCA1 and/or BRCA2 mutations. Between-group statistical comparison was performed. Results: In PET/CT performed for primary staging, patients with BRCA-positive BC had significantly higher SUVmax (p=0.039), larger tumor size (p=0.025), and presence of axillary nodal metastases (p=0.023) than patients with BRCA-negative BC. Although the Ki-67 index was higher in the BRCA-positive group than BRCA-negative group, this difference was not significant (p=0.157). Moreover, in the BRCA-positive and negative groups, SUVmax, Ki-67 index, and tumor size, grade, and stage were significantly correlated with each other. Conclusion: The results of this study showed a strong association between BRCA mutations and SUVmax, which indicates the poor prognosis of BC.

[Genetic constitution analysis of idiopathic sudden hearing loss]. / Idyopatik ani isitme kayipli olgularin genetik yapilarinin analizi.

OBJECTIVES: The purpose of this research is to understand the etiology of sudden hearing loss due to genetic factors in Turkish people. Determination of these genetic factors and better understanding of molecular pathogenesis may guide more realistic planning and treatment recommendations. PATIENTS AND METHODS: Forty patients (Group 1; 19 males, 21 females; mean age 37.9+/-15.6 years; range 9 to 76 years) who presented with sudden hearing loss to the Ear, Nose and Throat Clinic of Medical Faculty Hospital of Cumhuriyet University between January 2008 and June 2009, and were diagnosed with sudden hearing loss through history, physical examination and review of audiometric findings, and 20 healthy volunteers (Group 2; 14 males, 6 females; mean age 31.7+/-4.4 years; range 24 to 43 years) for the control group were included in this study. All Patients were evaluated by the genetic clinic for the GJB2, GJB3, GJB6 and WFS1 gene using multiplex ligation-dependent probe amplification (MLPA) method mutation analysis. RESULTS: No difference was found in the peripheral blood sample analyses of the two groups at WFS1 exon 8 and connexin 26, 30 and 31 gene zones using the MLPA method with respect to heterozygous mutation (p=0.291, p>0.05). In four patients in group 1 heterozygous mutation was detected at the target gene zone. Heterozygous mutation was in the WFS1 exon 8 zone in two patients; and in the WFS1 exon 1 zone in other two patients. CONCLUSION: Sudden hearing loss studies in the future should include connexin 26, connexin 30 and other gene mutations that may affect the function of the gap-junction located in the region of the cochlea stria vascularis (stV), basal membrane (BM), spiral limbus (Li) and spiral ligament (SL). These studies should be performed on larger series, and should include family members of patients with sudden hearing loss.

[The role of apoptosis and protective effect of carnitine in contralateral testicular injury in experimental unilateral testicular torsion]. / Deneysel tek tarafli testis torsiyonundaki karsi testis hasarinda apoptozisin rolü ve karnitinin koruyucu etkisi.

BACKGROUND: We examined the role of programmed cell death (PCD) in the etiology of contralateral testis injury as well as the protective effect of carnitine. METHODS: Thirty-six Wistar Albino rats were used in the study. Rats were divided into six groups as control, sham, torsion-detorsion with 6- and 24-hour intervals, and torsion-detorsion-carnitine administration with 6- and 24-hour intervals. The left testes of all rats were torsioned 720 degrees. Intraperitoneal carnitine was administered to groups as 100 mg/kg one hour before detorsion. Orchiectomy was applied to the contralateral testis a week after detorsion. Testes were examined with respect to diameters of seminiferous tubules (DST), ratios of malonyl dialdehyde and Johnsen biopsy scores (JBS), and PCD ratios. Results were evaluated by ANOVA test. RESULTS: Programmed cell death ratios were significantly higher in the torsion-detorsion with 6- and 24-hour intervals groups compared to the sham group. Those increases were more prominent in the torsion-detorsion with 24-hour interval group. DST and JBS of the control group were significantly higher than in the experimental groups (p < 0.05). The protective effect of carnitine was significant in the 24-hour torsion group, while no significant difference were detected in the 6-hour torsion-detorsion-carnitine group. CONCLUSION: Increased injury and PCD in the contralateral testis was observed with prolonged exposure time in this model. It was possible to decrease the injury with carnitine.