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Öğe Bialelic pathogenic (c.830g>a(p.r277q)) variant disrupting the GNE gene function and causes Nonaka myopathy phenotype(Pleiades Publishing Inc, 2023) Dogan, Mustafa; Akbulut, Ekrem; Gezdirici, Alper; Eroz, Recep; Bozdogan, Sevcan TugNonaka myopathy (MIM 605820) is caused by homozygous pathogenic variants in the GNE gene. It is a recessively inherited early adult-onset myopathy that usually preserves the quadriceps and presents with bilateral foot drop, usually caused by anterior tibialis weakness. In patients with Nonaka myopathy, serum creatine kinases are slightly elevated, muscle weakness progresses slowly, and ambulation loss develops after 15-20 yr. The current study aims to raise awareness of Nonaka myopathy that occurs as a rare phenotype due to pathogenic variants in GNE gene. Detailed family histories and clinical data were recorded. Whole exome sequencing was performed and co-segregation analysis of the family were done by Sanger sequencing. Also the homology model of the mutant protein was created with the ProMod3 algorithm. We identified a bialelic pathogenic variant (c.830G>A) in GNE gene, which explain the patients' clinical status. We present the main findings of two siblings with Nonaka myopathy together with detailed clinical and genetic profiles of the patients together with a three-dimensional mutant GNE protein model. We think that the clinical characteristics and the effect of the (c.830G>A) variant will facilitate our understanding of GNE gene in Nonaka myopathy pathogenesis.Öğe Clinical, radiological and computational studies on two novel GNPTG variants causing mucolipidosis III gamma phenotypes with varying severity(Springer, 2021) Dogan, Mustafa; Eroz, Recep; Terali, Kerem; Gezdirici, Alper; Bolu, SemihMucolipidosis III gamma (ML III gamma) is a slowly progressive disorder that affects multiple parts of the body such as the skeleton, joints, and connective tissue structures. It is caused by pathogenic variants in the GNPTG gene that provides instructions for producing the gamma subunit of GlcNAc-1-phosphotransferase. In this study we aim to characterize clinical findings and biological insights on two novel GNPTG variants causing ML III gamma phenotypes with varying severity. We report on two siblings with ML III gamma bearing the previously undescribed c.477C > G (p.Y159*) nonsense variant in a homozygous state as well as a patient with ML III gamma bearing the novel c.110 + 19_111-17del variant in a homozygous state. These variants were revealed by whole-exome sequencing and Sanger sequencing, respectively. Their parents, who are heterozygotes for the same mutation, are healthy. The clinical and radiographic presentation of ML III gamma in our patients who had c.477C > G (p.Y159*) variant is consistent with a relatively severe form of the disease, which is further supported by a working three-dimensional model of the GlcNAc-1-phosphotransferase gamma subunit. On the other hand, it is seen that our patient who carries the c.110 + 19_111-17del variant has a milder phenotype. Our findings help broaden the spectrum of GNPTG variants causing ML III gamma and offer structural and mechanistic insights into loss of GlcNAc-1-phosphotransferase gamma subunit function.Öğe Erkek İnfertilitesi ile Başvuran Hastalarda Spermiogram, Hormonal Profil ve Genetik Analiz Sonuçlarının Karşılaştırmalı Analizi: Tek Merkez Deneyimi(2022) Çiçek, Gülsemin; Gezdirici, Alper; Güleç, Elif Yılmaz; Ayaz, İbrahim Orkunt; Ünal, Işık; Eröz, RecepAmaç: Bu çalışmanın amacı, hastanemize infertilite nedeniyle başvuran erkeklere yardımcı üreme tekniklerinden önce uygun genetik danışmanlık verebilmek için, azospermi ve/veya oligozoospermi etiyolojisine yönelik standart sitogenetik yöntemler ve Y kromozom mikrodelesyon analizleri ile hem majör kromozom anomalilerinin hem de Y kromozomu mikrodelesyonlarının sıklığı ve tiplerini araştırmaktır. Gereç ve Yöntemler: Çalışmamıza 2017-2020 yılları arasında erkek infertilitesi nedeniyle Kanuni Sultan Süleyman Eğitim ve Araştırma hastanemize başvuran toplam 437 hasta dâhil edildi. Tüm hastalar spermiogram, hormonal profil, kromozom analizi ve Y mikrodelesyon analizleri doğrultusunda değerlendirildi. Bulgular: Çalışmamızda toplam 437 hastanın 42’sinde (%9,6) kromozomal anomaliler tespit edildi. En sık görülen kromozomal anomali 47,XXY(Klinefelter sendromu) idi. 5 hastamızda dengeli translokayonlar vardı. 1 hastada ise marker kromozom tespit edildi. Geriye kalan 395 hastanın kromozom analizi normaldi. 44 hastamızda (%10,06) ise AZF genleri üzerinde çeşitli y-kromozomu mikrodelesyonları saptandı. 1 hastada AZFa delesyonu, 4 hastada AZFb+c delesyonu, 17 hastada AZF-c gr/gr delesyonu, 2 hastada komplet AZFa+b+c delesyonu, 2 hastada komplet AZFc delesyonu, 1 hastada parsiyel AZFb delesyonu, 9 hastada kısmi AZFb+c delesyonu, 8 hastada parsiyel AZFc delesyonu tespit edildi. Geriye kalan 393 hastada herhangi bir Y kromozomu mikrodelesyonu saptanmadı. Sonuç: Mevcut bilgiler ve geçmişteki literatür çalışmaları eşliğinde özellikle şiddetli oligospermi ve azospermili hastalarda kromozom analizi ve Y mikro delesyonu analizlerini yardımcı üreme tekniklerinden önce önermekteyiz.Öğe An integrated clinical and molecular study of a cohort of Turkish patients with Marfan syndrome harboring known and novel FBN1 variants(Springernature, 2021) Gezdirici, Alper; Terali, Kerem; Gulec, Elif Yilmaz; Bornaun, Helen; Dogan, Mustafa; Eroz, RecepMarfan syndrome (MFS) is an autosomal dominant genetic condition that mainly affects connective tissue in many parts of the body. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. The diagnosis of MFS relies on the revised Ghent criteria, outlined by international expert opinion to facilitate accurate recognition of this syndrome as well as to improve patient management and counseling. However, it may not always be possible to make a definitive diagnosis according to these criteria in each patient and thus molecular confirmation is necessary in subjects with suspected MFS. This debilitating, if not fatal, disorder is caused by mutations in FBN1, which encodes a major constitutive element of extracellular microfibrils. Here, we present a detailed clinical and molecular analysis of 76 Turkish patients with definitive or suspected MFS diagnosed at our center between 2014 and 2019. We were able to identify a total of 51 different FBN1 variants in our cohort, 31 of which have previously been reported in the relevant scientific literature. The remaining 20 variants have not been documented to date. In one patient, we detected a large deletion including the entire FBN1 gene using the array CGH approach. Currently, there are very few studies on the genotype-phenotype correlation of patients with MFS, and no clear genotype-phenotype maps for MFS have been constructed so far, except for some cases. We believe that our findings will make a rich and peculiar contribution to the elusive genotype-phenotype relationship in MFS, especially in this large and populous ethnic group.Öğe Study of ten causal genes in Turkish patients with clinically suspected maturity-onset diabetes of the young (MODY) using a targeted next-generation sequencing panel(Springer, 2022) Doğan, Mustafa; Eröz, Recep; Bolu, Semih; Yüce, Hüseyin; Gezdirici, Alper; Arslanoğlu, İlknur; Terali, KeremBackground Maturity-onset diabetes of the young (MODY), which is the most common cause of monogenic diabetes, has an autosomal dominant pattern of inheritance and exhibits marked clinical and genetic heterogeneity. The aim of the current study was to investigate molecular defects in patients with clinically suspected MODY using a next-generation sequencing (NGS)-based targeted gene panel. Methods Candidate patients with clinical suspicion of MODY and their parents were included in the study. Molecular genetic analyses were performed on genomic DNA by using NGS. A panel of ten MODY-causal genes involving GCK, HNF1A, HNF1B, HNF4A, ABCC8, CEL, INS, KCNJ11, NEUROD1, PDX1 was designed and subsequently implemented to screen 40 patients for genetic variants. Results Ten different pathogenic or likely pathogenic variants were identified in MODY-suspected patients, with a diagnostic rate of 25%. Three variants of uncertain significance were also detected in the same screen. A novel pathogenic variant in the gene HNF1A (c.505_506delAA [p.Lys169AlafsTer18]) was described for the first time in this report. Intriguingly, we were able to detect variants associated with rare forms of MODY in our study population. Conclusions Our results suggest that in heterogenous diseases such as MODY, NGS analysis enables accurate identification of underlying molecular defects in a timely and cost-effective manner. Although MODY accounts for 2-5% of all diabetic cases, molecular genetic diagnosis of MODY is necessary for optimal long-term treatment and prognosis as well as for effective genetic counseling.Öğe Tekrarlayan Gebelik Kayıpları Nedeniyle Çalışılan 306 Çiftin Kromozom Analizi ve Trombofili Parametrelerinin Değerlendirilmesi: Tek Merkez Deneyimi(2022) Doğan, Mustafa; Eröz, Recep; Gezdirici, Alper; Yavaş, CüneydAmaç: Bu çalışmanın amacı, hastanemize tekrarlayan gebelik kaybı nedeniyle başvuran çiftlere uygun genetik danışmanlık verebilmek için hem majör kromozom anomalilerinin hem de trombofili parametrelerinin etiyolojideki rolünü araştırmaktır. Gereç ve Yöntemler: Çalışmamıza tekrarlayan gebelik kaybı nedeniyle Başakşehir Çam ve Sakura Şehir Hastanesi Genetik Hastalıklar Değerlendirme Merkezi'ne başvuran toplam 306 çift dâhil edildi. Tüm hastalarda kromozom analizleri ve 306 bayanda trombofili parametrelerinin analizleri gerçekleştirildi. Bulgular: Çalışmamızda toplam 306 çiftin 13’ünde (%4,25) polimorfizm dışında kalan kromozomal anomaliler tespit edildi. 4 hastada robertsonian translokasyon, 3 hastada resiprokal traslokasyon, 4 hastada mozaik kromozom kuruluşu, 1 hastada yapısal kromozal dengesizlik (derivatif kromozom) ve 1 hastada sayısal kromozal anomali varlığı tespit edilmiştir. Geriye kalan 293 çiftin kromozom analizi normaldi. Çalışmamızda trombofili parametreleri analiz edilen 306 bayan olgunun yaklaşık %10’unda Faktör V Leiden varyantı saptanırken, Faktör II G20210A varyantı ise yaklaşık %3,5 oranında saptanmıştır. 3 hastada (%1) Faktör V Leiden varyantı homozigot, 27 hastada ise Faktör V Leiden varyantı (%8,8) heterozigot olarak saptanmıştır. 10 hastanın (%3,3) Faktör II G20210A varyantını heterozigot olarak taşıdıkları saptanmıştır. Faktör II G20210A varyantını homozigot olarak taşıtan bir hasta çalışmamızda saptanmamıştır. Sonuç: Mevcut bilgiler ve geçmişteki literatür çalışmaları eşliğinde tekrarlayan gebelik kaybı nedeniyle değerlendirilen çiftlerde etiyolojiyi aydınlatmak için kromozom analizi ve trombofili parametrelerinin değerlendirilmesini ve bu parametrelerde ilişkili olduğu düşünülen bir neden saptandığında tedavi imkanları bulunduğundan dolayı özellikle yardımcı üreme tekniklerinden önce bu analizlerin yapılmasını önermekteyiz.
