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Öğe The Application of Next Generation Sequencing Maturity Onset Diabetes of the Young Gene Panel in Turkish Patients from Trakya Region(Galenos Yayincilik, 2021) Yalcintepe, Sinem; Comlek, Fatma Ozguc; Gurkan, Hakan; Demir, Selma; Atli, Emine Ikbal; Atli, Engin; Eker, DamlaObjective: The aim of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by targeted-gene sequencing of 20 genes related to monogenic diabetes, estimate the frequency and describe the clinical characteristics of monogenic diabetes and MODY in the Trakya Region of Turkey. Methods: A panel of 20 monogenic diabetes related genes were screened in 61 cases. Illumina NextSeq550 system was used for sequencing. Pathogenicity of the variants were assessed by bioinformatics prediction software programs and segregation analyses. Results: In 29 (47.5%) cases, 31 pathogenic/likely pathogenic variants in the GCK, ABCC8, KCNJ11, HNF1A, HNF4A genes and in 11 (18%) cases, 14 variants of uncertain significance (VUS) in the GCK, RFX6, CEL, PDX1, KCNJ11, HNF1A, G6PC2, GLIS3 and KLF11 genes were identified. There were six different pathogenic/likely pathogenic variants and six different VUS which were novel. Conclusion: This is the first study including molecular studies of twenty monogenic diabetes genes in Turkish cases in the Trakya Region. The results showed that pathogenic variants in the GCK gene are the leading cause of MODY in our population. A high frequency of novel variants (32.4%-12/37) in the current study, suggests that multiple gene analysis provides accurate genetic diagnosis in MODY.Öğe A case report: 13q21-qter deletion with digital anomalies, duodenal atresia and anal atresia(Springer, 2015) Ozen, Yasemin; Gurkan, Hakan; Ozbek, Ulfet Vatansever; Atli, Emine Ikbal; Eker, Damla; Acunas, Betul[Abstract Not Available]Öğe Comprehensive Genetic Analysis Results of TSC1/TSC2 Genes in Patients with Clinical Suspicion of Tuberous Sclerosis Complex and Definition of 3 Novel Variants(Galenos Publ House, 2021) Demir, Selma; Yalcintepe, Sinem; Atli, Engin; Yalcin, Yelda; Atli, Emine Ikbal; Eker, Damla; Karal, YaseminBackground: Tuberous Sclerosis Complex is an autosomal dominant multi-system disorder with an incidence of about 1 in 6000 live births. Defects in either TSC1 (* 605284) or TSC2 (* 191092) genes encoding the components of the Tuberous Sclerosis Complex are responsible for the disease. Therefore, consideration of TSC1/TSC2 pathogenic variations is recommended in the updated diagnostic criteria of Tuberous Sclerosis Complex. Aims: To present the TSC1/TSC2 screening results of a mixed patient population as well as possible new variants in 23 cases from 20 different families who were referred to our Genetic Diseases Diagnosis Center with the signs and symptoms of Tuberous Sclerosis Complex. Study design: Retrospective, cross-sectional study. Methods: Germline TSC1/TSC2 variants were screened in DNA samples extracted from peripheral blood samples of 23 patients from 20 unrelated families using targeted high-throughput sequencing and multiplex ligation-dependent probe amplification methods. The variants identified were classified according to ACMG 2015 guidelines. Results: In total, 5 different pathogenic/likely pathogenic changes have been defined. All these pathogenic/likely pathogenic variants were located in the TSC2 gene. Three of the pathogenic/likely pathogenic variants were novel. Two patients who are twin sisters were found to have TSC2/PKD1 contiguous deletion syndrome. One of the 3 novel variants was a mosaic in-frame deletion. We did not identify any pathogenic variants of the TSC1 gene. Conclusion: The novelty of most of the variants found, including a mosaic likely pathogenic variant, and the presence of a large genomic rearrangement, supports the importance of a comprehensive approach in analyzing TSC1/TSC2 genes. Genetic diagnosis should be performed with caution, considering the possibility of mosaic variants with low allelic fractions.Öğe Customised targeted massively parallel sequencing enables more precisely diagnosis of patients with epilepsy(Wiley, 2022) Atli, Emine Ikbal; Atli, Engin; Yalcintepe, Sinem; Demir, Selma; Kalkan, Rasime; Eker, Damla; Gurkan, HakanBackground Advancement in genetic technology has led to the identification of an increasing number of genes in epilepsy. This will provide a lot of information in clinical practice and improve the diagnosis and treatment of epilepsy. Aim To show the importance of genes in the next-generation sequencing (NGS) panel during the evaluation of epilepsy and to emphasise the importance of genetic studies in different populations for the evaluation of genes that cause disease. Methods This was a single-centre retrospective cohort study of 80 patients who underwent NGS testing with a customised epilepsy panel. Results In a total of 54 (67.5%) out of 80 patients, pathogenic or likely pathogenic variants and variants of uncertain significance (VOUS) were identified according to the American College of Medical Genetics and Genomics criteria. Pathogenic or likely pathogenic variants (n = 35) were identified in 29 (36.25%) out of 80 individuals. VOUS (n = 34) were identified in 28 (35%) out of 80 patients. Pathogenic, likely pathogenic and VOUS were most frequently identified in TSC2 (n = 11), SCN1A (n = 6) and TSC1 (n = 5) genes. Other common genes were KCNQ2 (n = 3), AMT (n = 3), CACNA1H (n = 3), CLCN2 (n = 3), MECP2 (n = 2), ASAH1 (n = 2) and SLC2A1 (n = 2). Conclusions NGS-based testing panels contribute to the diagnosis of epilepsy and might change the clinical management by preventing unnecessary and potentially harmful diagnostic procedures and management in patients. Thus, our results highlight the benefit of genetic testing in children suffering with epilepsy.Öğe The Frequency of SMN1, SMN2 Copy Numbers in 246 Turkish Cases Analyzed with MLPA Method(Thieme Medical Publ Inc, 2023) Yalcintepe, Sinem; Karal, Yasemin; Demir, Selma; Atli, Emine Ikbal; Atli, Engin; Eker, Damla; Mail, CisemThis study aimed to define the copy numbers of SMN1 and SMN2 genes and the diagnosis rate and carrier frequency of spinal muscular atrophy (SMA) in the Thrace region of Turkey. In this study, the frequency of deletions in exons 7 and 8 in the SMN1 gene and SMN2 copy numbers were investigated. A total of 133 cases with the preliminary diagnosis of SMA and 113 cases with the suspicion of being an SMA carrier from independent families were analyzed by multiplex ligation-dependent probe amplification method for SMN1 and SMN2 gene copy numbers.SMN1 homozygous deletions were detected in 34 patients (25.5%) of 133 cases with the suspicion of SMA. Cases diagnosed with SMA type I was 41.17% (14/34), 29.4% (10/34) with type II, 26.4% (9/34) with type III, and 2.94% (1/34) with type IV. The SMA carrier rate was 46.01% in 113 cases. In 34 SMA cases, SMN2 copy numbers were: two copies - 28 cases (82.3%), three copies - 6 cases (17.6%). SMN2 homozygous deletions were detected in 15% (17/113) of carrier analysis cases. The consanguinity rate of the parents was 23.5% in SMA diagnosed cases. In this study, we had a 25.5% of SMA diagnosis rate and 46% SMA carrier frequency. The current study also showed the relatively low consanguinity rate of the Thrace region, with 23.5% according to the east of Turkey.Öğe THE FREQUENCY OF Y CHROMOSOME MICRODELETIONS AND CYTOGENETIC ABNORMALITIES IN CASES WITH MALE INFERTILITY FROM THRACE REGION: SINGLE CENTER EXPERIENCE(Istanbul Univ, Fac Medicine, Publ Off, 2021) Yalcintepe, Sinem; Eker, Damla; Gurkan, HakanObjective: Genetic factors, including Y chromosome microdeletions, are responsible for about 10% of male infertility cases and are particularly associated with azoospermia or severe oligozoospermia. In our study, it was aimed to determine the frequency of Y chromosome microdeletions in the Thrace region and to provide information about the heterogeneous phenotype in infertile male patients with AZF microdeletion. Material and Method: Chromosome analysis and Y chromosome microdeletion analysis were performed on 446 male patients with non-obstructive azoospermia or oligozoospermia, who applied to the Trakya University Hospital Medical Genetics Department Genetic Diseases Diagnosis Center clinic between the years 2011-2019. Results: Y chromosome microdeletion was detected in 19 (4.26%) of 446 cases. Structural chromosomal anomalies were accompanied in 5 of 19 cases with Y chromosome microdeletions. Three hundred fifty-two cases had no Y chromosome microdeletion, 35 (9.94%) of these cases had Klinefelter syndrome, 1 (0.28%) case had Klinefelter syndrome low grade mosaicism, 3 (0.85%) cases had Robertsonian translocation carriage, and 1 (0.28%) had Reciprocal translocation carriage. Conclusion: Y chromosome microdeletion screening in non-obstructive azoospermic or oligosoospermic infertile male patients has prognostic value and affects clinical prognosis. The results of our study support the proposal to perform Y chromosome microdeletion analysis before microTESE in azoospermic or oli-gosoospermic infertile male patients as reported in the literature.Öğe A Genetics Study in the Foreskin of Boys with Hypospadias(Karger, 2023) Inanc, Irem; Avlan, Dincer; Eker, Damla; Gurkan, HakanIntroduction: Hypospadias is a malformation of the genitourinary system in males, characterized by the placement of the urethral opening in the ventral surface of the penis. Although controversies continue about etiology, endocrine disrupting chemicals that disrupt normal endocrine signaling at the receptor or signal transduction level are thought to play an essential role in etiology. This study aimed to investigate the receptor gene expressions of the sex hormones and FGFR2, HOXA13, and TGFB1, which are considered to play an essential role in developing hypospadias. Methods: The samples from the foreskin of 26 patients with hypospadias and 26 healthy children who underwent circumcision operations were collected. ESR1, AR, FGFR2, HOXA13, and TGFB gene expressions were investigated by real-time PCR in samples obtained during surgery. Results: In the hypospadias group, ESR1 expression was increased (p = 0.013), and AR and FGFR2 expressions were decreased, which were found to be statistically significant (p = 0.027 and p = 0.003, respectively). There was no statistically significant difference between hypospadias and control groups in TGFBand HOXA13expression levels (p > 0.05). Discussion: The results suggest that sex hormone receptors and FGFR2 may play an essential role in developing male external genital structures at the gene level. The defects in the expression of these genes can contribute to understanding the development of hypospadias.Öğe Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma(Codon Publications, 2021) Yalcintepe, Sinem; Gurkan, Hakan; Korkmaz, Fatma Nur; Demir, Selma; Atli, Engin; Eker, Damla; Guler, Hazal SezginerThe aim of this study was to evaluate germline variant frequencies of pheochromocytoma and paraganglioma targeted susceptibility genes with next-generation sequencing method. Germline DNA from 75 cases were evaluated with targeted next-generation sequencing on an Illumina NextSeq550 instrument. KIF1B. RET, SDHB, SDHD, TMEM127, and VHL genes were included in the study, and Sanger sequencing was used for verifying the variants. The pathogenic/likely pathogenic variants were in the VHL, RET, SDHB, and SDHD genes, and the diagnosis rate was 24% in this study. Three different novel pathogenic variants were determined in five cases. This is the first study from Turkey, evaluating germline susceptibility genes of pheochromocytoma and paraganglioma with a detection rate of 24% and three novel variants. All patients with pheochromocytoma and paraganglioma need clinical genetic testing with expanded targeted gene panels for higher diagnosis rates.Öğe HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ(2021) Atlı, Emine İkbal; Gürkan, Hakan; Eker, DamlaAMAÇ: Hipotoni, uzuvlarda, gövdede veya kraniyofasiyal iskelet kaslarında azalmış tonusu belirtmek için kullanılan genelbir terimdir. Doğumda veya daha sonra çocukluk dönemindetespit edilebilir. Tanıyı koymak, prognozu öngörebilmek, tedavistratejileri ve ailenin daha sonra doğacak çocukları için tekrarlama riskini belirlemek açısından önemlidir. Nörolojik muayeneve beyin görüntülemesine ek olarak konvansiyonel sitogenetik,moleküler sitogenetik ve moleküler genetik testler klinik tanıyıdesteklemek açısından önemlidir. Hipotoni, minor veya majormalformasyonlarla ve bilişsel yetersizlik ile birlikte olduğu za- man otozomal kromozom anormallikleri düşünülmelidir. Arala- rında klinik farklılıklar bulunan değişik kromozom anormallikle- ri ve sendromlarda atipik yüz görünümü, el ve ayakta dismorfikbulgular veya diğer organ malformasyonları bulunabilir. Genetik testlerdeki son gelişmeler, moleküler tanıların daha da genişleyen yelpazesi spinal müsküler atrofi, konjenital miyotonikdistrofi, Prader-Willi sendromu ile hastalık altında yatan mutasyonların (konjenital kas distrofileri ve birkaç konjenital miyopati) tanımlanması, bu semptomu olan çocuklara spesifik tanıimkanı sağlar.GEREÇ VE YÖNTEM: Çalışmamıza Trakya Üniversitesi Hastanesi, Tıbbi Genetik Anabilim Dalı, Genetik Hastalıklar Tanı Merkezipolikliniğine 2017-2019 yılları arasında hipotoni klinik ön tanısıile birlikte müracaat eden 47 çocuk hasta dâhil edildi. Hasta genomik DNA’ları ile array-karşılaştırmalı genomik hibridizasyon(aCGH) çalışması gerçekleştirildi.BULGULAR: 47 hastanın 12’sinde (%25,53) 557kb ila 40 Mbarası büyüklükte kopya sayısı değişimleri (CNV) saptandı. Tespitedilen kopya sayısı varyantları, Genomik Varyantlar Veritabanı(DGV), Ensembl kaynakları Genomik Varyasyon ve Fenotip Veritabanı (DECIPHER), Sitogenomik Diziler için Uluslararası Standartlar (ISCA) ve Klinik olarak ilgili varyant veritabanlarının yorumlarının genel arşivi veritabanları ile literatür taramalarındanaraştırılarak değerlendirilmiştir.SONUÇ: Yenidoğan ve infantil dönemde hipotoni nedenleriarasında yer alan tablolar, genetik sendromlar, kas hastalıkları,kranial malformasyonlar, metabolik hastalıklar özellikle peroksizomal ve mitokondriyal hastalıklardır. Bu grup hastalıklar arasında ayırıcı tanısı yapabilmek için EMG, Kranial MR ve kas biopsisigibi invazif testler uygulanır. Sonuç olarak, yenidoğan ve infantil döneminde ciddi hipotoni varlığında hastanın genetik açıdan değerlendirilmesi, sebebi bilinmeyen hipotoninin nedeninioluşturan pek çok hastalığın tanısı için yapılacak gereksiz invasiftestlerin yükünden hastayı kurtarabilir. Erken tanı, ayrıca, hastalığa özgü ortaya çıkabilecek problemlerden korunma ve erkentedavisi açısından da bir o kadar önemlidir. Hastalığın erkendönemde tanısını koymak, hastanın rehabilitasyonuna dahaerken başlama imkânı sağlayacağından önem arz etmektedir.Öğe Identification of a Novel KIF11 Variant p.(Leu804Thrfs Ter13) in a Case with Isolated Microcephaly(Wolters Kluwer Medknow Publications, 2022) Yalcintepe, Sinem; Guler, Hazal Sezginer; Zhuri, Drenushe; Eker, Damla; Gurkan, HakanMicrocephaly is a rare neurological condition, and it is characterized by a smaller head than other children of the same age and sex. Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MLCRD) is a syndrome with a varying spectrum that occurs as a result of variants of KIF11 gene. A 3-year-old girl was presented to our clinic with microcephaly; she had no motor or growth retardation except microcephaly. After obtaining a normal karyotype and microarray result, Trusight One-Expanded Panel analysis showed NM_004523.4 (KIF11): c. 2409dupA (p. Leu804Thrfs Ter13) heterozygous pathogenic novel variant. Patients who have KIF11 mutation often also have different clinical features; in our case, the motor development is consistent with its peers and has a history of prenatal and postnatal microcephaly. Microcephaly can be caused by a variety of genetic mutations. In our case, firstly we identify the association of a novel de novo KIF11 gene duplication variant related to isolated microcephaly.Öğe Inherited Variants is a Genetic Determinant of Mercaptopurine/Methotrexate Intolerance in Children With Acute Lymphoblastic Leukemia(2022) Atli, Emine Ikbal; Eker, Damla; Atlı, Engin; Demir, Selma; Yalçıntepe, Sinem; Gürkan, Hakan; Eren, TubaObjectives: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children with distinctive features across its different subtypes. Although the etiology of ALL has not been fully elucidated, it has been shown that the onset of ALL is partly due to genetic factors. Genes related to drug transport, metabolism, detoxification and DNA repair could influence the cytotoxic effects associated with chemotherapy, including those involved in the transport (e.g., ABCB1, ABCC2, MTHFR and SLCO1B3), and transporter of folate (SLC19A1) of MTX and 6-MP. Likewise, genes involved in DNA-binding transcription factor activity and RNA polymerase II cis-regulatory region sequence-specific DNA binding (NR3C1) and DNA repair (TYMS) have previously been linked with cytotoxicity of 6-MP and/or MTX. Methods: In the current study, we therefore aimed to assess prior associations for 17 selected genetic variants in 5 genes, in a large cohort of 41 ALL patients treated with mercaptopurine (6-MP) and methotrexate (MTX) combination therapy or mono-therapy of whom detailed clinical toxicity datas were available. Results: Among the 17 variants in 5 genes evaluated according to the results of our study, the polymorphisms in rs2893881 (G/A) in ARID5B were closely related to therapy toxicity. To our knowledge, the effect of ARID5B variants on childhood ALL has not been studied in Turkey. Several genome-wide and candidate gene association studies have reported strong associations between ARID5B SNPs and risk of ALL and toxicity to therapeutic drugs in different populations. Conclusion: Finally, one of the most significant findings from this study is that ARID5B germline SNPs related to ALL treatment toxicity. To our knowledge, this is the first report to describe the relationship between ARID5B and ALL treatment response in the context of a preliminary ALL clinical trial. Further investigation of ARID5B variation in line with different ALL treatment regimens is required to improve its value as a prognostic marker.Öğe Investigating the Genetic Etiology of Pediatric Patients with Peripheral Hypotonia Using the Next-Generation Sequencing Method(Thieme Medical Publ Inc, 2022) Eker, Damla; Gurkan, Hakan; Karal, Yasemin; Yalcintepe, Sinem; Demir, Selma; Atli, Engin; Karasalihoglu, Serap T.Background Hypotonia occurs as a result of neurological dysfunction in the brain, brainstem, spinal cord, motor neurons, anterior horn cells, peripheral nerves, and muscles. Although the genotype-phenotype correlation can be established in 15 to 30% of patients, it is difficult to obtain a correlation in most cases. Aims This study was aimed to investigate the genetic etiology in cases of peripheral hypotonia that could not be diagnosed using conventional methods. Methods A total of 18 pediatric patients with peripheral hypotonia were included. They were referred to our genetic disorders diagnosis center from the Pediatric Neurology Department with a prediagnosis of hypotonia. A custom designed multigene panel, including ACTA1 , CCDC78 , DYNC1H1 , GARS , RYR1 , COL6A1 , COL6A2 , COL6A3 , FKRP , FKTN , IGHMBP2 , LMNA , LAMA2 , LARGE1 , MTM1 , NEM , POMGnT1 , POMT1 , POMT2 , and SEPN1 , was used for genetic analysis using next-generation sequencing (NGS). Results In our study, we found 13 variants including pathogenic (two variants in LAMA2) and likely pathogenic variants (three variants in RYR1 and POMGnT1) and variants of uncertain clinical significance (eight variants in RYR1, COL6A3, COL6A2, POMGnT1 and POMT1) in 11 (61%) out of 18 patients. In one of our patients, a homozygous, likely pathogenic c.1649G > A, p.(Ser550Asn) variant was defined in the POMGnT1 gene which was associated with a muscle-eye-brain disease phenotype. Conclusion The contribution of an in-house designed gene panel in the etiology of peripheral hypotonia with a clinical diagnosis was 5.5%. An important contribution with the clinical diagnosis can be made using the targeted multigene panels in larger samples.Öğe The investigation of killer cell immunoglobulin-like receptor genotyping in patients with systemic lupus erytematosus and systemic sclerosis(Springer London Ltd, 2016) Tozkir, Julide Duymaz; Tozkir, Hilmi; Gurkan, Hakan; Donmez, Salim; Eker, Damla; Pamuk, Gulsum Emel; Pamuk, Omer NuriSystemic lupus erythematosus (SLE) is an autoimmune disease characterised by the production of autoantibodies and the involvement of multiple organ systems. Systemic sclerosis (SSc) is another autoimmune disease that causes fibrosis. We will aim to analyse the role of killer cell immunoglobulin-like receptor (KIR) genotypes and their existence with the respective HLA ligands in patients with SLE and SSc. Forty-five SLE, 25 SSc and 40 healthy controls were included. We examined the presence/absence of KIR2DL1, 2DL2, 2DL3, 2DL4, 2DL5A, 2DL5B, 2DS1, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1, 2DP1, 3DP1 and their known HLA ligands. In the SLE group, the KIR2DL5, KIR2DL5B and KIR2DS3 genes were significantly more frequent, and KIR2DL3 gene was significantly less than in controls (p values < 0.05). In SSc patients, the KIR2DS3 gene was more frequent than in controls (p = 0.032). The KIR2DL3 gene was detected more frequently in controls while KIR2DS3 gene was more frequent in the patient group when SLE and SSc patients were combined (p values < 0.05). The KIR2DS2/HLA-C and KIR2DS2/HLA-C combinations were significantly more in both SLE and SSc groups than in controls. The KIR2DL2 and KIR2DL5B genes were protective from neurologic involvement in SLE patients (p values < 0.05). The variations of some KIR genes such as KIR2DL5, KIR2DL5B, KIR2DS3 and KIR2DL3 may have a role in the pathogenesis of SLE and SSc. Also, the presence of KIR2DL2 and KIR2DL5B may cause major organ involvement, like neurologic involvement, in SLE.Öğe Investigation of the Genetic Etiology in Idiopathic Generalized Epileptic Disorders by Targeted Next-generation Sequencing Technique(Galenos Publ House, 2023) Atli, Engin; Gurkan, Hakan; Guldiken, Baburhan; Eker, Damla; Yalcintepe, Sinem; Demir, Selma; Atli, Emine IkbalBackground: Idiopathic generalized epilepsy is the most common group of epilepsy disorders in children and adolescents. Various types of genetic abnormality were identified among the hereditary factors that explain epilepsy. Aims: To determine the variations in the etiopathogenesis, treatment protocol planning, and prognosis of idiopathic generalized epilepsy using the next-generation sequencing method.Study Design: A cross-sectional study. Methods: This study included 32 patients with idiopathic generalized epilepsy. Genomic DNA was obtained from peripheral venous blood samples taken from the patients. A total of 18 genes encoding ion channel subunits that are involved in monogenic disorders and are associated with idiopathic generalized epilepsy were included. The targeted custom next-generation sequencing panel was designed to cover all coding exons and all exon/intron splice site regions of 18 genes.Results: We detected 9 (28%) variations, including 1 likely pathogenic (a variant in the SCN1A gene) and 8 of unknown clinical significance (2 in the CLCN2 genes, GABBR2, SCN1B, SLC2A1, SLC4A10 genes, and 2 in the TBC1D24 gene).Conclusion: Study results should be supported by functional advanced studies, with increased existing knowledge in the relevant variations.Öğe Investigation of the Relationship Between Genome Wide Association Studies-derived Polymorphisms and Differentiated Thyroid Cancer Risk in a Turkish Population(Gazi Univ, Fac Med, 2021) Demir, Selma; Gurkan, Hakan; Celik, Mehmet; Sezer, Atakan; Eker, Damla; Guldiken, Sibel; Sut, NecdetBackground: Thyroid cancer is the most common malignancy of endocrine system. Genome Wide Association Studies (GWAS) revealed a number of common variants associated with thyroid cancer risk. In this study, we aimed to investigate the association of these known variants with thyroid cancer risk in a Turkish population living in Trakya region. Methods: The study included 97 cases of differentiated thyroid cancer and 379 healthy controls. Real-Time Polymerase Chain Reaction (RT-PCR) method was used for the genotyping of rs965513, rs944289, rs966423 rs2439302 polymorphisms. Results: There was no statistically significant difference between patients and controls in terms of SNP genotype and allele frequencies. The distribution of cumulative genetic risk scores between patients and controls was also not significantly different. In the multiple logistic regression analysis (MLR), it was observed that the relationship of rs2439302 polymorphism GG genotype with thyroid cancer risk has a trend to be significant ((p = 0.067, 95%CI: 2.947 (0.928-9.357)). Conclusion: We suggest that the confirmation of the association of common variants with thyroid cancer in different populations will contribute to make a consensus on global risk alleles. The marginal significance of the association of rs2439302 with thyroid carcinoma risk shown in our study supports the need for functional studies on the role of this polymorphism in thyroid carcinoma.Öğe Investigation on the Effects of Modifying Genes on the Spinal Muscular Atrophy Phenotype(Thieme Medical Publ Inc, 2022) Zhuri, Drenushe; Gurkan, Hakan; Eker, Damla; Karal, Yasemin; Yalcintepe, Sinem; Atli, Engin; Demir, SelmaIntroduction Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by the degeneration of motor neurons, muscle weakness, and atrophy that leads to infant's death. The duplication of exon 7/8 in the SMN2 gene reduces the clinical severity of disease, and it is defined as modifying effect. In this study, we aim to investigate the expression of modifying genes related to the prognosis of SMA like PLS3 , PFN2 , ZPR1 , CORO1C , GTF2H2 , NRN1 , SERF1A , NCALD , NAIP , and TIA1. Methods Seventeen patients, who came to Trakya University, Faculty of Medicine, Medical Genetics Department, with a preliminary diagnosis of SMA disease, and eight healthy controls were included in this study after multiplex ligation-dependent probe amplification analysis. Gene expression levels were determined by real-time reverse transcription polymerase chain reaction and delta-delta CT method by the isolation of RNA from peripheral blood of patients and controls. Results SERF1A and NAIP genes compared between A group and B + C + D groups, and A group of healthy controls, showed statistically significant differences ( p = 0.037, p = 0.001). Discussion PLS3, NAIP , and NRN1 gene expressions related to SMA disease have been reported before in the literature. In our study, the expression levels of SERF1A , GTF2H2 , NCALD , ZPR1 , TIA1 , PFN2 , and CORO1C genes have been studied for the first time in SMA patients.Öğe Myricetin'in radyoprotektif etkisinin mikronukleus yöntemiyle in vitro şartlarda incelenmesi(Trakya Üniversitesi Sağlık Bilimleri Enstitüsü, 2013) Eker, Damla; Pala, Funda SibelGünümüzde radyasyon, birçok hastalığın tanı ve tedavisinde kullanılmaktadır. Ancak sağaltım amacıyla da olsa, uygulanan radyasyon, genetik materyalde doza bağlı olarak hasarlar meydana getirebilmektedir. Hasarlar ya doğrudan radyasyonun DNA'yı hasarlaması ya da dolaylı yoldan ortamdaki su molekülleri ile etkileşerek serbest radikaller oluşturmasıyla meydana gelir. Oluşan hasarların bazıları farklı DNA tamir mekanizmaları ile onarılabildiği gibi bazıları onarılamayacak seviyede olabilir. Bu nedenle radyasyon hasarını azaltmak amacıyla hastalara bazı koruyucu ajanlar verilmektedir. Bu koruyucu ajanlar radyasyonun verilen dozunu düşürerek tedavi sürecinde istenmeyen bir etki oluşturabilse de sağlam dokuların radyasyon hasarından korunabilmesi için kullanılmalarının gerekli olduğu durumlar vardır. Myricetin, bitkisel kaynaklı doğal bir flavonoid olup antioksidan özelliği olduğu bilinen bir maddedir. Bu nedenle radyasyon sonucu oluşan serbest radikalleri kendine bağlayarak DNA'da oluşacak oksidatif hasarı engelleyebileceği beklenmektedir. DNA'da oluşan hasarları belirlemek için, farklı dozimetrik yöntemler kullanılmaktadır. Mikronukleus (MN) analiz yöntemi de, oluşan DNA hasarının belirlenmesinde ve DNA hasarına karşı hücrede oluşan yanıtın incelenmesinde kullanılan bir tekniktir. MN'lar, binukleat (BN) hücreler ile aynı sitoplazma içinde bulunan, hücre bölünmesi sırasında mitotik iğdeki hatalar nedeniyle kutuplara çekilemeyen kromozomlardan ve/veya kromozom parçalarından oluşmaktadır. Radyasyonun oluşturduğu hasarlar da MN analizi ile incelenebilmektedir. Bu çalışmada, yapısında bulunan OH ekleri sayesinde güçlü bir antioksidan olarak bilinen myricetinin farklı radyasyon dozlarında, radyasyon öncesi ya da sonrasında kullanılmasının MN sıklığı üzerine etkileri incelendi. Farklı konsantrasyonlardaki myricetinin 2 Gray (Gy) ve 4 Gy radyasyon öncesi ve sonrasında MN sıklığı üzerine etkileri değerlendirildi. Farklı radyasyon dozlarında, 100 µM ve 200 µM konsantrasyonlarında uygulanan myricetinin MN sıklığını azalttığı görüldü. Radyasyon öncesi ve sonrasında uygulanan myricetin ise MN sıklığında istatistiksel olarak anlamlı bir fark oluşturmadı (P>0.05). Uygulanan myricetin konsantrasyonlarında radyasyon dozunun azaldığı ancak bu azalmanın gruplar arasında anlamlı bir fark oluşturmadığı bulundu. Radyasyon öncesi ve sonrası arasında fark bulunmadığı için myricetinin antioksidan etkisinden daha çok, DNA tamirini uyararak etki ettiği ya da radyasyon sonucu hücrede oluşan hasar miktarına göre hücreyi apoptoza götürdüğü düşünüldü. Birden fazla MN taşıyan BN hücrelerin sayısı azalırken, kromozom aberasyon taşımayan hücrelerin sayısı değişmedi. Bu çalışmanın sonucu olarak, kanser hastalarında myricetinin radyoterapi tedavisine ek olarak kullanılabilmesi için daha ileri çalışmaların yapılması gerektiği önerilmektedir.Anahtar Kelimeler: Myricetin, mikronukleus, DNA hasarı, radyoprotektif etkiÖğe Periferal hipotoni tanılı çocuk hastalarda genetik etiyolojinin yeni nesil dizi analizi yöntemi ile araştırılarak, fenotip-genotip ilişkisinin belirlenmesi(Trakya Üniversitesi, 2020) Eker, Damla; Gürkan, HakanHipotoni, beyin, beyin sapı, spinal kord, motor nöronlar, ön boynuz hücreleri, periferik sinirler ve kaslarda nörolojik fonksiyon bozukluğu sonucu ortaya çıkan nörolojik bir bulgudur. Üst ve alt ekstremitelerde, gövdede ya da kraniyofasiyal iskelet kaslarında azalan tonusu ifade etmek için yaygın olarak kullanılmaktadır. Hipotonik olguların %60 kadarını genetik-metabolik etiyolojilerin oluşturduğu ve bunların önemli bir bölümünün genetik hastalıklardan kaynaklandığı bildirilmiştir. Tüm hipotonik olguların %15-30'unu oluşturan periferal hipotoni olgularında genetik sonuçlar ile klinik bulgular desteklenebilse de tüm olgularda fenotip-genotip ilişkisi kurulamamaktadır. Çalışmamızın amacı, konvansiyonel sitogenetik, moleküler sitogenetik ve Multiplex Ligation-dependent Probe Amplification yöntemleri uygulanarak tanı konulamayan periferal hipotoni olgularında, periferal hipotoni ile ilişkili olduğu düşünülen genleri içeren, özgün tasarlanmış çoklu gen paneli (ACTA1, CCDC78, DYNC1H1, GARS, RYR1, COL6A1, COL6A2, COL6A3, FKRP, FKTN, IGHMBP2, LMNA, LAMA2, LARGE1, MTM1, NEM, POMGnT1, POMT1, POMT2, SEPN1) kullanılarak yeni nesil dizi analizi (NGS) teknolojisiyle genetik etiyolojinin araştırılmasıdır. Çalışmaya Trakya Üniversitesi Sağlık Araştırma ve Uygulama Merkezi Çocuk Nöroloji Bilim Dalı Polikliniğinden hipotoni ön tanısı ile Tıbbi Genetik Anabilim Dalı Genetik Hastalıklar Tanı Merkezine yönlendirilen, klasik sitogenetik ve moleküler yöntemler ile nedeni açıklanamayan, periferal hipotoniye sahip 18 hasta (6 ay ile 7 yaş arasında) dahil edildi. Çalışmamızda 18 hastanın 11'inde (%61) on üç varyant saptandı. Bu varyantlardan ikisi LAMA2, biri COL6A2, üçü COL6A3, üçü RYR1, biri POMT1 ve üçü POMGnT1 genlerinde yer almaktadır. ACMG-2015 kriterlerine göre on üç varyantın ikisi patojenik, üçü muhtemel patojenik, sekizi klinik önemi belirsiz varyant olarak değerlendirildi. Nedeni açıklanamayan periferal hipotoniye sahip bir hastamızda POMGnT1 geninde homozigot, c.1649G>A, p.(Ser550Asn) varyasyonu saptandı. Bu varyasyon literatürde Kas-Göz-Beyin (MEB) Hastalıkları fenotipi ile ilişkilendirilmiştir. Hastamıza ait fizik muayene bulguları ve görüntüleme sonuçları incelendiğinde, hastanın kliniğinin MEB fenotipi ile uyumlu olduğu görüldü. Diğer bir hastamızda ise RYR1 geninde daha önce literatürde ve açık erişimli veri tabanlarında rapor edilmeyen, "klinik önemi belirsiz" olarak sınıflandırılan yeni bir varyasyon saptandı. Ülkemizde hipotonik olguların belirli algoritmalar kullanılarak tanımlanmasına yönelik farklı çalışmalar olmakla birlikte, nedeni açıklanamayan periferal hipotoni olgularının NGS yöntemiyle genetik etiyolojisinin araştırılmasına yönelik bir başka çalışma literatürde bildirilmemiştir. Özgün tasarlanmış gen paneli ile nedeni açıklanamayan periferal hipotoniye sahip on sekiz hastamızın birinde tespit edilen varyasyon, hastanın fenotipi ile uyumlu olarak saptandı. Bu sonuçlara göre, periferal hipotoni etiyolojisinde özgün tasarlanmış gen panelinin klinik tanıya katkı oranı % 5,5'tir. Sonuç olarak, hedefe yönelik tasarlanmış çoklu gen panelinin daha uzun zaman dilimi içerisinde, örneklem büyüklüğünün arttırılarak NGS yöntemi ile çalışılması durumunda, klinik tanıya önemli katkılar sağlayacağı öngörüsündeyiz.Öğe The Phenotypic Spectrum of Desanto-Shinawi Syndrome: A Comparative Report of the First Reported Case in Turkey(Mary Ann Liebert, Inc, 2024) Mail, Cisem; Yalcintepe, Sinem; Eker, Damla; Gurkan, HakanDeSanto-Shinawi syndrome (DESSH, OMIM #616708) is a rare genetic disorder caused by pathogenic variants in the WAC gene. This syndrome is characterized by a wide range of physical and neurological symptoms including dysmorphic features, developmental delay, intellectual disability, and behavioral abnormalities. DESSH was described by DeSanto in 2015, and since then, only a few dozen cases have been reported worldwide. Recent research has focused on identifying the underlying genetic cause of the syndrome as well as exploring potential treatments. In this report, we describe a female case who had dysmorphic features including long palpebral fissures, depressed nasal root, mild bulbous nasal tip, thin upper lip, hypertrichosis, short fingers, and intellectual disability, speech delay, and motor retardation. In addition, she had behavioral abnormalities such as agitation, anxiety, and attention deficit hyperactivity disorder (ADHD). Clinical exome sequencing showed a pathogenic heterozygous nonsense variant in exon 13 of the WAC gene c.1837C>T, p.(Arg613Ter) with de novo inheritance. To the best of our knowledge, this is the first case of DESSH reported from Turkey. We aimed to report this rare syndrome and compare the clinical findings of our case with previously reported cases in the literature.Öğe A Pilot Study about Clinical Features of Aberrations Chromosome 22q(Thieme Medical Publ Inc, 2022) Atli, Emine Ikbal; Atli, Engin; Yalcintepe, Sinem; Demir, Selma; Mail, Cisem; Eker, Damla; Ozen, YaseminObjective A significant number of genetic variations have been identified in chromosome 22, using molecular genetic techniques. Various genomic disorders on chromosome 22, including cat's eye syndrome caused by extra copies of the proximal region of the 22q chromosome, are now well-defined. Our aim in the study was to show phenotypic variability associated with rearrangements of the 22q chromosomal region. Methods We focused our study on clinical aspects of these disorders, including genetic testing, genotype-phenotype correlation, and potential treatments. A total of 998 patients were referred for genetic analysis (Karyotyping, MLPA, array-CGH) during January 2015 to February 2020 because of intellectual deficiency, behavior issues, and/or multiple congenital abnormalities in several genetics departments. Informed consent was obtained from all the patients and/or their parents. Results 22q11.21 or 22q13.33 microdeletions and 22q11.22-q11.23 microduplication were identified in 31 patients out of referrals. The 22q aberrations were detected in 31/998 patients, giving a prevalence of 3.1%. In this study, 18 patients with 22q11.2 (LCR22A-H) deletion, three patients with 22q13.31 deletion, 9 patients with 22q11.2 duplication and one patient with 22q13.31 duplication were identified. We report on the clinical and molecular characterization of 31 individuals with distal deletions and duplications of chromosome 22q. Conclusions The current study demonstrated in the largest postnatal case series reporting the whole spectrum of atypical phenotypic and genotypic variations at 22q. We believe that when all the phenotypic differences are taken into account, various anomalies including developmental delay and intellectual disability might be considered as an indication to search for aberrations of 22q along with congenital heart diseases.
