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    A case report of a patient with neurodevelopmental disorder with impaired speech and hyperkinetic movements: A biallelic variant in the ZNF142 gene
    (Wiley, 2024) Kaya, Derya; Köse, Canan Ceylan; Akcan, Mehmet Berkay; Sılan, Fatma
    Biallelic pathogenic variations in the zinc finger protein 142 (ZNF142) gene are associated with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM). This disorder is characterized by developmental delay, intellectual disability, speech delay, and movement disorders such as dystonia, tremor, ataxia, and chorea. Here, we report a patient who exhibited common neurological features and rarely reported brain MRI findings. Exome sequencing identified a novel biallelic variant in ZNF142 (c.3528_3529delTG; p.C1176fs*5 (NM_001105537.4)). NEDISHM was first described by Khan et al. (2019) and has been reported in 39 patients to date. Furthermore, upon reviewing our in-house data covering 750 individuals, we identified three different pathogenic ZNF142 variants. It appears that the frequency of ZNF142 alleles is not as low as initially thought, suggesting that this gene should be included in new generation sequencing panels for similar clinical scenarios. Our goal is to compile and expand upon the clinical features observed in NEDISHM, providing novel insights and presenting a new variant to the literature. We also aim to demonstrate that ZNF142 pathogenic variants should be considered in neurodevelopmental diseases.
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    Anemia and thrombocytopenia due to a novel BRPF1 variant in a family from canakkale with intellectual disability and dysmorphic facies: Case report and review of the literature
    (John Wiley and Sons Inc, 2023) Köse, Canan Ceylan; Kaya, Derya; Akcan, Mehmet Berkay; Sılan, Fatma
    Intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) (MIM#617333) is an autosomal dominant disorder characterized by delayed psychomotor development, intellectual disability (ID), and dysmorphic facial features due to pathogenic variations in the Bromodomain- and PHD Finger-Containing Protein (BRPF1) (MIM#602410) gene. Herein, we report the first Turkish patients with IDDDFP. Additionally, the patients had hematopoietic disorders such as anemia and thrombocytopenia, which have not been previously described in IDDDFP patients. Genetic testing using Whole Exome Sequencing (WES) revealed a novel heterozygous c.1433G > A; p.W478* (NM_004634.3) pathogenic variant on exon 3 of the BRPF1 gene. The patients demonstrated classical features of IDDDFP such as intellectual disability, developmental delay, ptosis, micro and retrognathia, and dysmorphic facial features, in addition to the anemia and thrombocytopenia. Apart from the variant in BRPF1, no additional genomic changes were detected by WES and chromosomal microarray analysis (CMA). Hopefully, our novel report on the hematopoietic anomalies of our patients due to BRPF1 will expand upon the clinical spectrum of IDDDFP, encourage further studies about BRPF1-hematopoietic system relations, and affect the diagnostic and therapeutic schemes of hematopoietic system disorders.
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    BRCA2 genindeki klinik önemi bilinmeyen varyantların patojenitesinin in silico analizler ile değerlendirilmesi ve klinik korelasyonu
    (Çanakkale Onsekiz Mart Üniversitesi, 2024) Köse, Canan Ceylan; Sılan, Fatma
    GİRİŞ VE AMAÇ: BRCA2 geni, DNA onarımı ve tümör baskılayıcı özellikleriyle meme ve over kanserleri gibi malignitelerle ilişkilidir. BRCA2'deki klinik önemi bilinmeyen varyantlar (VUS), kanser risk değerlendirmelerinde belirsizliklere yol açmaktadır. Bu çalışmada, Çanakkale Onsekiz Mart Üniversitesi Tıbbi Genetik Polikliniği'nde yeni nesil dizileme ile tespit edilen BRCA2 VUS varyantlarının patojenitesinin in siliko analizlerle değerlendirilmesi ve klinik korelasyonlarının incelenmesi amaçlanmıştır. YÖNTEM: VUS varyantlarının genomik analizleri Franklin, ClinVar ve QCI veritabanlarında incelenirken, protein üzerindeki etkiler SIFT, MutationTester2021, FATHMM, PANTHER ve AlphaMissense gibi in siliko araçlarla değerlendirilmiştir. PHD-SNP ve SNPs&GO, varyantların hastalıkla ilişkisini incelemek için kullanılmış; MUpro ve I-Mutant ise protein stabilizasyonu tahmininde uygulanmıştır. HOPE ve Swiss-Model ile 3D modelleme yapılarak varyantların yapısal etkileri görselleştirilmiştir. İn siliko analiz sonuçları, hastaların kanser öyküleri ve aile geçmişiyle ilişkilendirilmiştir. BULGULAR: Çalışmada BRCA2 geninde toplam 193 varyant tespit edilmiş; bunların %53'ü benign/muhtemel benign, %21'i patojenik/muhtemel patojenik, %24'ü ise VUS olarak sınıflandırılmıştır. VUS olarak belirlenen 48 varyant in siliko analizler ile incelenmiştir. Hepsi missense türünde olan bu varyantların en sık ekzon 11'de bulunduğu tespit edilmiştir. İn siliko analizlerde, 7 varyant patojenik/muhtemel patojenik, 29 varyant ise benign/muhtemel benign olarak sınıflandırılmıştır. Çelişkili sonuçlar nedeniyle 12 varyant net olarak sınıflandırılamamıştır. Ayrıca, çalışmada 7 novel varyant saptanmıştır. SONUÇ: İn siliko analizler, BRCA2 VUS varyantlarının patojenitelerini belirlemede etkili olmuştur. Çalışma sonucunda VUS oranı %24'ten %6'ya düşürülmüş, bu da in siliko analizlerin klinik uygulamalar için önemini ortaya koymuştur. Gelecekteki çalışmaların, varyantların işlevsel etkilerine odaklanarak BRCA2'nin kanser riskindeki rolünü daha iyi anlamamıza katkı sağlaması beklenmektedir. Anahtar Kelimeler: BRCA2, VUS, in siliko, klinik korelasyon
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    Exploring and Expanding Secondary Findings Through Exome Sequencing in the Turkish Population
    (Wiley, 2025) Akcan, Mehmet Berkay; Köse, Canan Ceylan; Çelik, Kübra Müge; Tekin, Koray; Kaya, Derya; Sılan, Fatma
    Introduction Exome-sequencing (ES) methods enable accurate diagnosis in challenging cases and uncover secondary findings (SFs) potentially linked to life-threatening or preventable diseases. The American College of Medical Genetics and Genomics (ACMG) publishes a list detailing which SFs should be reported and regularly updates it. We aimed to compare results across different SF versions in patients and explore additional SFs to identify potential new recommendations for SF reporting. Methods We conducted a retrospective analysis of 724 patients to identify ACMG SFs using the QIAGEN Clinical Insight (QCI) Interpret database. Furthermore, we investigated pathogenic/likely pathogenic variants in cancer and cardiovascular disease genes not listed in ACMG SFs, as well as genes associated with common diseases prevalent in our country. Methods ACMG SF v3.2 variants were identified in 56 patients (7.7%), with no observed differences between ACMG v3.1 and v3.2. Additionally, our analysis revealed that 208 patients harbored non-ACMG SF variants. Conclusion In this study, we focused on known SFs and identified additional variants that could be considered as new recommendations. While expanding the list of SFs can pose challenges during analyses and genetic counseling, a thoughtfully curated SF list has the potential to enhance patient care and improve clinical outcomes.
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    Spinal muscular atrophy carrier screening program: awareness and attitude of healthcare professionals in Turkey
    (Springer Heidelberg, 2024) Çelik, Kübra Müge; Köse, Canan Ceylan; Kaya, Derya; Tekin, Koray; Sılan, Fatma
    Spinal Muscular Atrophy (SMA) is an autosomal recessive disease caused by variants in the SMN1 gene, leading to progressive muscle weakness. The carrier frequency of SMN1 gene variants, including variant and copy number variations, is estimated to be around 1 in 50 people, while the global prevalence of SMA is 1-3 per 10,000 live births. In response to the increasing carrier proportion, especially due to consanguineous marriages, Turkey launched the SMA Carrier Screening Program in 2021. Notably, recent SMA cases have been observed in the children of healthcare workers who did not undergo carrier screening, prompting us to evaluate their awareness of this program. After receiving ethics approval, 1,322 healthcare professionals completed a 15-item survey based on the SMA Carrier Screening Guidelines. Of these, 5.8% were unaware of SMA, and 26% lacked information about the national screening program. Awareness of the screening program was significantly lower among secondary and tertiary healthcare professionals compared to primary healthcare professionals (p < 0.0001) and among non-physician healthcare professionals compared to physicians (p < 0.0001). Additionally, a serious lack of knowledge was observed concerning the parts of the screening covering the pregnancy period. Although there is generally high awareness of the SMA Carrier Screening Program among healthcare professionals, significant knowledge gaps exist. These findings highlight the need for increased efforts to more effectively deliver screening programs and continue the education of healthcare professionals. Education and awareness campaigns can enhance program awareness and effectiveness, reach wider audiences, and contribute to preventive measures for the health of future generations.