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    Analysis of ACE2 and TMPRSS2 coding variants as a risk factor for SARS-CoV-2 from 946 whole-exome sequencing data in the Turkish population
    (Wiley, 2022) Duman, Nilgun; Tuncel, Gulten; Bisgin, Atil; Bozdogan, Sevcan Tug; Sag, Sebnem Ozemri; Gul, Seref; Kiraz, Aslihan
    Heterogeneity in symptoms associated with COVID-19 in infected patients remains unclear. ACE2 and TMPRSS2 gene variants are considered possible risk factors for COVID-19. In this study, a retrospective comparative genome analysis of the ACE2 and TMPRSS2 variants from 946 whole-exome sequencing data was conducted. Allele frequencies of all variants were calculated and filtered to remove variants with allele frequencies lower than 0.003 and to prioritize functional coding variants. The majority of detected variants were intronic, only two ACE2 and three TMPRSS2 nonsynonymous variants were detected in the analyzed cohort. The main ACE2 variants that putatively have a protective or susceptibility effect on SARS-CoV-2 have not yet been determined in the Turkish population. The Turkish genetic makeup likely lacks any ACE2 variant that increases susceptibility to SARS-CoV-2 infection. TMPRSS2 rs75603675 and rs12329760 variants that were previously defined as common variants that have different allele frequencies among populations and may have a role in SARS-CoV-2 attachment to host cells were determined in the population. Overall, these data will contribute to the formation of a national variation database and may also contribute to further studies of ACE2 and TMPRSS2 in the Turkish population and differences in SARS-CoV-2 infection among other populations.
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    Consistency of variant interpretations among bioinformaticians and clinical geneticists in hereditary cancer panels
    (Springernature, 2022) Agaoglu, Nihat Bugra; Unal, Busra; Dogan, Ozlem Akgun; Kanev, Martin Orlinov; Zolfagharian, Payam; Sag, Sebnem Ozemri; Temel, Sehime Gulsun
    Next-generation sequencing (NGS) is used increasingly in hereditary cancer patients' (HCP) management. While enabling evaluation of multiple genes simultaneously, the technology brings to light the dilemma of variant interpretation. Here, we aimed to reveal the underlying reasons for the discrepancy in the evidence titles used during variant classification according to ACMG guidelines by two different bioinformatic specialists (BIs) and two different clinical geneticists (CGs). We evaluated final reports of 1920 cancer patients and 189 different variants from 285 HCP were enrolled to the study. A total of 173 of these variants were classified as pathogenic (n = 132) and likely pathogenic (n = 41) by the BI and an additional 16 variants, that were classified as VUS by at least one interpreter and their classification would change the clinical management, were compared for their evidence titles between different specialists. The attributed evidence titles and the final classification of the variants among BIs and CGs were compared. The discrepancy between P/LP final reports was 22.5%. The discordance between CGs was 30% whereas the discordance between two BIs was almost 75%. The use of PVS1, PS3, PP3, PP5, PM1, PM2, BP1, BP4 criteria markedly varied from one expert to another. This difference was particularly noticeable in PP3, PP5, and PM1 evidence and mostly in the variants affecting splice sites like BRCA1(NM_007294.4) c.4096 + 1 G > A and CHEK2(NM_007194.4) c.592 + 3 A > T. With recent advancements in precision medicine, the importance of variant interpretations is emerging. Our study shows that variant interpretation is subjective process that is in need of concrete definitions for accurate and standard interpretation.
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    The Importance of Multiple Gene Analysis for Diagnosis and Differential Diagnosis in Charcot Marie Tooth Disease
    (Turkish Neurosurgical Soc, 2021) Yalcintepe, Sinem; Gurkan, Hakan; Dogan, Ipek Gungor; Demir, Selma; Sag, Sebnem Ozemri; Kabayegit, Zehra Manav; Atli, Emine Ikbal
    AIM: To investigate the genetic etiology of Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN). MATERIAL and METHODS: We herein examined 55 non-related patients with a suspicion of CMT phenotype or HMSN using a customized multigene panel based on the next-generation sequencing technique. All cases were previously analyzed for PMP22 duplication with the Multiplex Ligand Probe Amplification (MLPA) method. RESULTS: In 13 cases (7.15%), we identified a pathogenic/likely pathogenic variant. The affected genes were MARS1, NDRG1, GJB1, GDAP1, MFN2, PRX, SH3TC2, and FGD4. In six cases (10.9%), novel variants were identified: pathogenic variants in GJB1 and FGD4 genes, variants of unknown significance (VUS) in HSPB3, CHRNA1, ARHGEF10, and KIF5A genes. In 21 cases (11.55%), VUS with the genes HSPB3, KIF1B, SCN11A, CHRNA1, HSPB1, FIG4, ARHGEF10, DHTKD1, SBF1, EGR2, SBF2, IGHMBP2, KIF5A, and DNAJB2 were identified. CONCLUSION: In this study, we had a 7.15% diagnosis rate with the NGS (Next Generation Sequencing) method in the CMT disease. Targeted next-generation sequencing panels are beneficial, time-saving, and cost-effective in the diagnosis of CMT.
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    A Novel PHEX Mutation in A Case Followed Up with A Diagnosis of X-linked Hypophosphatemic Rickets
    (Galenos Publ House, 2023) Demirbas, Ozgecan; Eren, Erdal; Öngen, Yasemin Denkboy; Sag, Sebnem Ozemri; Gürkan, Hakan; Temel, Sehime Gulsun
    Introduction: X-linked hypophosphatemic is a result of a mutation which leads to loss of function in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene. The case is here presented of a patient followed up for XLH rickets, with the formation of a stop code through frame-shifting mutation in the PHEX gene. Case Report: An 18-month old male infant presented at our clinic with the complaint of curvature in the legs. In the physical examination of the infant, height was measured as 78 cm (-1.67 SDS) and weight was 12.5 kg (0.52 SDS). Deformity was present in the frontal protusion, the wrist widths and the legs. Laboratory test results were determined as phosphorus: 2.3 mg/dL (n=3.5-4.7), calcium: 9.8 mg/dL (n=8.5-10.5), alkaline phosphatase (ALP) 707 IU/L (n=40-150), 25(OH) D vitamin:18 mu g/L (n=18-40), PTH: 79 pg/mL (n=15-68), and tubular phosphorus reabsorption was low (71%). Visualisation on wrist radiographs of collapse in the metaphyseal sections of the radus and ulna and metaphyseal irregularity. Conventional treatment was started. Next generation sequence analysis of the proband revealed the presence of a hemizygous c.281_288delTTCCCGAA (p.lle94ArgfsTER14) frameshift variant in PHEX gene. This novel variant is pathogenic according to the ACMG criteria, and not reported in any database before. While full-fill clinical recovery was not achieved with conventional treatment and some complications occured, Burosumab treatment was started. Conclusion: Here presented of a patient who was diagnosed with XLH, and was then determined with a novel mutation in the PHEX gene. The current treatment options directed at the basic pathology render genetic diagnosis more important in cases of hypophosphatemic rickets.