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Öğe Clinical and genetic features of L1 syndrome patients: Definition of two novel mutations(Elsevier Science Bv, 2018) Isik, Esra; Onay, Huseyin; Atik, Tahir; Akgun, Bilcag; Cogulu, Ozgur; Özkınay, FerdaL1 syndrome is a rare X linked recessive disorder caused bygene mutations in the L1 cell adhesion molecule (L1CAM), and characterized by hydrocephalus, intellectual disability, adducted thumbs and spasticity of the legs. The gene encodes a protein which plays an important role in neuronal development. Two unrelated L1 syndrome cases, with global developmental delay and hydrocephalus, were referred to pediatric genetics subdivision for genetic counseling. Bilateral adducted thumbs and spasticity in the lower extremities were also observed in both patients. Molecular analysis revealed two novel hemizygous mutations in the patients: a deletion mutation (c.749delG; p.Ser250Thrfs*51) and a splicing mutation (c.3166 + 1G > A). To conclude; in male patients with intellectual disability and hydrocephalus, where adducted thumbs are present, L1 syndrome should be considered.Öğe Clinical and molecular findings in children and young adults with persistent low alkaline phosphatase concentrations(Sage Publications Inc, 2021) Araci, Mehmet Bilal; Akgun, Bilcag; Atik, Tahir; Isik, Esra; Gunes, Ak; Barutcuoglu, Burcu; Ozkinay, FerdaBackground Hypophosphatasia is a rare inherited metabolic disease resulted by ALPL gene mutations. It is characterized by defective bone and teeth mineralization. The phenotypic spectrum is highly variable ranging from lethal perinatal form to mild forms which are only diagnosed in adulthood or remain undiagnosed despite persistently low concentrations of ALP. The aim of this study is to evaluate the clinical phenotype and frequency of ALPL mutations in a group of patient with hypophosphatasaemia. Methods Thirty individuals with alkaline phosphatase values below 40 IU/L in at least two assessments and having no alternative explanation for their low ALP concentrations were included in the study. The clinical features and radiological data of the study group were re-investigated for hypophosphatasia-related findings. ALPL sequence analysis was performed using Sanger sequencing. Results No patient in the study group had severe symptoms, nor had they initially been diagnosed as having hypophosphatasia. Four different heterozygous ALPL mutations (c.542C>T, c.648 + 1G>A, c.657G>T and c.862 + 1G>C) were found in four patients. One splice site mutation (c.862 + 1G>C) was reported for the first time in this study. Conclusion ALPL sequence analysis may help to diagnosing genetic defects in individuals with persistently low ALP concentrations and provide to take preventive measures before symptoms appear. As in the other populations, HPP displays allelic heterogeneity in our population.Öğe Evaluation of CNTNAP2 gene rs2107856 polymorphism in Turkish population with pseudoexfoliation syndrome(Springer, 2019) Karaca, Irmak; Yilmaz, Suzan Guven; Palamar, Melis; Onay, Huseyin; Akgun, Bilcag; Aytacoglu, Burcu; Aykut, Ayca; Özkınay, Feristah FerdaPurposeTo investigate rs2107856 single-nucleotide polymorphism (SNP) of CNTNAP2 gene in Turkish population with pseudoexfoliation and to correlate clinical characteristics with the genotypic profile.Materials and methodsForty-three patients with pseudoexfoliation syndrome (PXS), 46 patients with pseudoexfoliation glaucoma (PXG) and 99 healthy controls were enrolled. Comprehensive ophthalmological examination, central corneal thickness measurement and retinal nerve fiber layer thickness analysis of the peripapillary area were performed. Blood samples of 2mL with EDTA were obtained and sent for genetic analysis. The role of the detected polymorphism on disease tendency along with the genotype and allele frequencies in each group was evaluated.ResultsThe mean age of the groups was 70.08.0 (range 51-86) in PXS, 71.2 +/- 8.8 (range 51-93) in PXG and 64.6 +/- 8.3 (range 51-91) in controls. The percentages of homozygote individuals were 11.6, 10.9, 21.2%, and heterozygote individuals were 41.9, 45.7, 42.4% in patients with PXS, PXG and controls, respectively. There was no statistically significant difference between groups in terms of both genotype and allele frequencies of rs2107856 (p=0.429 and p=0.178, respectively). Retinal nerve fiber layer thickness did not differ between SNP-positive and SNP-negative individuals in PXG, and there was no significant difference between genotype and age, sex, best corrected visual acuity, intraocular pressure, central corneal thickness, cup/disk ratio and retinal nerve fiber layer thickness in any of the groups (p>0.05).Conclusion rs2107856 SNP of CNTNAP2 gene has no association with PXS and PXG in the evaluated Turkish population.Öğe Evaluation of Six Patients with Chromosome 18 Structural Anomalies and Novel Findings(Galenos Yayincilik, 2020) Isik, Esra; Akgun, Bilcag; Atik, Tahir; Özkınay, Ferda; Cogulu, OzgurAim: Structural chromosome 18 anomalies are characterized by multiple congenital anomalies and intellectual disability. in this study, 6 cases with structural anomalies of chromosome 18 diagnosed by using conventional and molecular cytogenetic analyses are presented. Materials and Methods: Six cases who were carrying structural chromosome 18 abnormalities were enrolled in the study. Developmental milestones, growth parameters and dysmorphologic features were evaluated by experienced clinical geneticists. Laboratory analysis including genetic tests, imaging studies, and eye and hearing examinations were obtained from the medical records, retrospectively. Results: All cases had karyotype analysis, 2 cases had fluorescence in situ hybridization analysis and one case had microarray analysis, which were performed by using peripheral blood. A total of 6 cases in which del (18p) in one case, del (18q) in 4 cases and i (18q) in one case were evaluated. Conclusion: Although a wide range of phenotypic findings, depending on the affected chromosomal region and size, can be seen in patients who carry structural chromosome 18 anomalies, some additional novel features are presented in our series which will contribute to the literature.Öğe Immunodeficiency in a Child with Alstrom Syndrome(Springer India, 2018) Ozdemir, Taha Resid; Karaca, Neslihan Edeer; Marshall, Jan Davis; Kutukculer, Necil; Aksu, Guzide; Ozgul, Riza Koksal; Ozanturk, Aysegul; Isik, Esra; Akgun, Bilcag; Ozdemir, Hamiyet Hekimci; Darcan, Sukran; Özkınay, Ferda; Cogulu, OzgurÖğe Molecular Genetic Diagnosis with Targeted Next Generation Sequencing in a Cohort of Turkish Osteogenesis Imperfecta Patients and their Genotype-phenotype Correlation(Galenos Publishing House, 2024) Ozen, Samim; Goksen, Damla; Evin, Ferda; Isik, Esra; Onay, Huseyin; Akgun, Bilcag; Ata, Aysun; Atik, Tahir; Ozkinay, Ferda; Darcan, Sukran; Cogulu, OzgurObjective: Osteogenesis imperfecta (OI) consists of a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. The aim was to investigate the molecular genetic etiology and determine the relationship between genotype and phenotype in OI patients using targeted next-generation sequencing (NGS). Methods: A targeted NGS analysis panel (Illumina TruSight One) containing genes involved in collagen/bone synthesis was performed on the Illumina Nextseq550 platform in patients with a confirmed diagnosis of OI. Results: Fifty-six patients (female/male: 25/31) from 46 different families were included. Consanguinity was noted in 15 (32.6%) families. Based on Sillence classification 18 (33.1%) were type 1 OI, 1 (1.7%) type 2, 26 (46.4%) type 3 and 11 (19.6%) type 4. Median body weight was -1.1 (-6.8, - 2.5) standard deviation scores (SDS), and height was -2.3 (-7.6, - 1.2) SDS. Bone deformity affected 30 dentinogenesis imperfecta (DI), and 2 (3.6%) had hearing loss. Disease-causing variants in COL1A1 and COL1A2 were found in 24 (52.1%) and 6 (13%) families, respectively. In 8 (17.3%) of the remaining 16 (34.7%) families, the NGS panel revealed disease-causing variants in three different genes ( FKBP10, SERPINF1, and P3H1). Nine (23.6%) of the variants detected by NGS panel had not previously been reported and were also classified as pathogenic based on American College of Medical Genetics guidelines pathogenity scores. In ten (21.7%) families, a disease-related variant was not found in any of the 13 OI genes on the panel. Conclusion: Genetic etiology was found in 38 (82.6%) of 46 families by targeted NGS analysis. Furthermore, nine new variants were identified in known OI genes which were classified as pathogenic by standard guidelines.Öğe A Novel Molecular Indicator for Inhibitor Development in Haemophilia A(Galenos Yayincilik, 2021) Isik, Esra; Mehdiyeva, Humay; Akgun, Bilcag; Kose, Timur; Kavakli, Kaan; Ozkinay, Ferda; Atik, TahirAim: Previous studies have reported inhibitor development (ID) risk in those patients who have hemophilia A (HA) with missense mutations to be 3-10%. We investigated the association between ID risk and various features of missense mutations; including the impact directly related to amino acid group change. Materials and Methods: Missense mutations in the F8 gene, clinical findings of the patients including severity of HA, and ID status were obtained from the F8 gene variant database (http://www.factorviii-db.org/). Twenty amino acids were then classified into groups according to their side chains. All information regarding each specific mutation, as well as any impact of the mutation on the amino acid group change, was recorded. Additionally, localization (at which domain) of any changed amino acid in the F8 protein was noted. Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), Mendelian Clinically Applicable Pathogenicity and Deleterious Annotation using Neural Networks scores were applied to identify a significant cut-off value indicative of ID. Results: Three variations were identified that could be considered as useful in the prediction of ID in mild HA. The first being that among mild HA patients, 7.9% (n=70/883) with mutations causing no amino acid group changes showed ID. This rate, however, was only 2.9% in patients with mutations leading to amino acid group changes. Secondly; in patients with mutations causing no amino acid group changes affecting A2, A3 and C2 domains, ID risk was found to be higher than in patients with mutations leading to amino acid group changes. Thirdly; an association between ID and CADD and REVEL scores was observed. Conclusion: In mild HA patients, the characteristics of missense mutations in terms of amino acid group changes, and CADD and REVEL scores could be of considerable utility in the prediction of ID risk.Öğe The Role of Molecular Karyotyping in the Genetic Etiology of Autism(Turkiye Sinir Ve Ruh Sagligi Dernegi, 2017) Ozbaran, Burcu; Akgun, Bilcag; Kacamak, Duygu; Kose, Sezen; Kavasoglu, Aysenur; Onay, HuseyinObjective: The aim of this study was to investigate the deletions and duplications with a molecular karyotyping technique and to elucidate the etiology of autism. Method: A total of 31 patients (20 boys and 11 girls) between 4 to 18 years old with normal chromosomal analysis and no Fragile X mutation were diagnosed in the Ege University Child and Adolescent Psychiatry Clinic with autism (according to DSM-IV-TR criteria) and were enrolled in the study. Symptom severity of the patients was evaluated with a Childhood Autism Rating Scale. Blood samples (EDTA collected) were obtained in order to extract DNA. Whole genome molecular karyotyping analyses were performed with Illumina IScan system by chips, which can scan 330.000 Single Nucleotid Polymorphisms (SNPs) to detect structural anomalies with a 10-kb resolution. Results: All patients had copy number variations (CNV) that sized between 20-kb and 3-Mb. All detected CNVs were analyzed by the help of KaryoStudio software and DGV database. The ones which might be causal and pathogenic were selected. Pathogenic CNVs (7 deletions, 2 duplications) were detected in 9 patients (29%). Conclusion: As a result, this is the first study whereby a molecular karyotyping technique was successfully used in autism patients in Turkey. Moreover, an intermediate resolution of 330.000 SNP chips were proven to be efficient for molecular karyotyping analysis.Öğe Targeted Molecular Genetic Diagnosis by Next Generation Sequence Analysis Method and Investigation of Responsible Candidate Genes in Patients with Osteogenesis Imperfecta(Karger, 2019) Ozen, Samim; Goksen, Damla; Isik, Esra; Gurkan, Ferda Evin; Onay, Huseyin; Akgun, Bilcag; Ata, Aysun; Atik, Tahir; Özkınay, Ferda; Darcan, Sukran; Cogulu, Ozgur
