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Öğe Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome(Elsevier B.V., 2023) Aksu Uzunhan, Tuğçe; Ertürk, Biray; Aydın, Kürşad; Ayaz, Akif; Altunoğlu, Umut; Yarar, Murat Hakkı; Gezdirici, Alper; İçağasıoğlu, Dilara Füsun; Gökpınar İli, Ezgi; Uyanık, Bülent; Eser, Metin; Kutbay, Yaşar Bekir; Topçu, Yasemin; Kılıç, Betül; Bektaş, Gonca; Arduç Akçay, Ayfer; Ekici, Barış; Chousein, Amet; Avcı, Şahin; Yüksel, Atıl; Kayserili, HülyaObjective: Joubert syndrome is a neurodevelopmental disorder with a distinctive hindbrain malformation called molar tooth sign, causing motor and cognitive impairments. More than 40 genes have been associated with Joubert syndrome. We aim to describe a group of Joubert syndrome patients clinically and genetically emphasizing organ involvement. Methods: We retrospectively collected clinical information and molecular diagnosis data of 22 patients with Joubert syndrome from multiple facilities. Clinical exome or whole-exome sequencing were performed to identify causal variations in genes. Results: The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. Multi-systemic organ involvement was observed in nine (40%) patients, with the eye being the most common, including Leber's congenital amaurosis, ptosis, and optic nerve coloboma. Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. The HYLS1 gene, which commonly causes hydrolethalus syndrome 1, was also associated with Joubert syndrome in one of our patients. A mild phenotype with hypophyseal hormone deficiencies without the classical molar tooth sign was observed with compound heterozygous and likely pathogenic variants not reported before in the KATNIP gene. Conclusion: Some rare variants that display prominent genetic heterogeneity with variable severity are first reported in our patients. In our study of 22 Joubert syndrome patients, CPLANE1 is the most affected gene, and Joubert syndrome as a ciliopathy is possible without a classical molar tooth sign, like in the KATNIP gene-affected patients.Öğe Clinical and molecular genetic findings of Crisponi/cold-induced sweating syndrome (CS/CISS) spectrum in patients from Turkey(Wiley, 2022) Yılmaz Güleç, Elif; Turgut, Gözde Tutku; Gezdirici, Alper; Karaman, Volkan; Öztürk, Fatma Nihal; Avcı, Şahin; Kalaycı, Tuğba; Şentürk, Leyli; Ayaz, Akif; Kayserili, Hülya; Uyguner, Zehra Oya; Altunoğlu, UmutCrisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type-3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype-phenotype relationships in CS/CISS-like spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread. CRLF1-associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7-related phenotypes.Öğe Diagnostic value of microarray method in autism spectrum disorder, intellectual disability, and multiple congenital anomalies and some candidate genes for autism: Experience of two centers(Galenos Publishing House, 2022) Ayaz, Akif; Gezdirici, Alper; Yılmaz Güleç, Elif; Özalp, Özge; Köseoğlu, Abdullah Hüseyin; Doğru, Zeynep; Yalçıntepe, SinemObjective: This study aimed to demonstrate the diagnostic value of microarray testing in autism spectrum disorder, intellectual disability, and multiple congenital anomalies of unknown etiology, as well as to report some potential candidate genes for autism. Methods: Microarray analysis records between January 2016 and December 2017 from two Genetic Diagnostic Centers in Turkey, Kanuni Sultan Suleyman and Adana Numune Training and Research Hospital, were compiled. Detected copy number variations (CNVs) were classified as benign, likely benign, variants of uncertain significance (VUS), likely pathogenic, and pathogenic according to American College of Medical Genetics and Genomics guidelines. The clinical findings of the some patients and the literature data were compared. Results: In 109 (24.5%) of 445 patients, a total of 163 CNVs with reporting criterion feature were detected. Sixty-nine (42%) and 8 (5%) of these were evaluated as pathogenic and likely pathogenic, respectively. Fifteen (9%) CNVs were also evaluated as VUS. Pathogenic or likely pathogenic CNVs were detected in 61 (13.6%) of 445 patients. Conclusions: We found that the probability of elucidating the etiology of microarray method in autism spectrum disorder, intellectual disability, and multiple congenital anomalies is 13.6% with a percentage similar to the literature. We suggest that the MYT1L, PXDN, TPO, and AUTS2 genes are all strong candidate genes for autism spectrum disorders. We detailed the clinical findings of the cases and reported that some CNV regions in the genome may be associated with autism.Öğe Effects of chromosomal translocations on sperm count in azoospermic and oligospermic cases(Dokuz Eylül University Institute of Health Sciences, 2022) Ayaz, Akif; Yalçıntepe, Sinem; Özalp, Özge; Yılmaz Güleç, Elif; Gezdirici, Alper; Akçay, Ebru Perim; Köseoğlu, Abdullah HüseyinPurpose: A number of mechanisms have been proposed for the effect of chromosomal translocations on spermatogenesis and sperm maturation. However, there are still numerous ambiguous issues regarding these two processes. The aim of this study is to evaluate the effect of chromosome break areas on sperm count in the light of the literature. Material and Methods: The study was conducted on the data of 16 male patients with reciprocal or Robertsonian translocation among 152 patients who were admitted to Adana Numune Training and Research Hospital and Kanuni Sultan Suleyman Training and Research Hospital Genetic Diagnosis Centers between 2013 and 2016 due to azoospermia and oligospermia. Results: 11 of these patients had reciprocal and five patients had Robertsonian translocations. All the patients with Robertsonian translocations were detected with azoospermia. Of the patients with reciprocal translocation, five of them were azoospermic and six of them were severe oligospermic. Conclusion: A total of 21 chromosomal breakpoints were identified in the 11 patients with reciprocal translocations. These chromosomal breakpoints may contribute to the clarification of ambiguous issues related to spermatogenesis and sperm maturation. The results also showed the importance of genetic counselling in patients with translocations.Öğe Fetal left ventricular myocardial performance index measured at 11–14 weeks of gestation in fetuses with an increased nuchal translucency(Wiley, 2023) Sezer, Salim; Oğlak, Süleyman Cemil; Kaya, Başak; Behram, Mustafa; Gedik Özköse, Zeynep; Süzen Çaypınar, Sema; Acar, Züat; Gezdirici, Alper; Bornaun, HelenObjective: This study aimed to evaluate the effect of an increase in nuchal translucency (NT) thickness on the myocardial performance index (MPI) in fetuses without cardiac anomaly in the first trimester and to determine whether a difference in MPI between those with and without trisomy 21 in these fetuses could be determined. Methods: The study group consisted of 53 pregnancies complicated with increased NT thickness without any associated structural anomalies. Forty-six gestational age-matched pregnant women whose fetuses had normal NT thickness were enrolled as the control group. Results: In the increased NT thickness group, the mean isovolumetric relaxation time (IRT) value (0.050 ± 0.011 s) was significantly higher and the mean ejection time (ET) value (0.149 ± 0.010 s) was significantly lower than those values in the normal NT thickness group (0.045 ± 0.005 and 0.155 ± 0.009 s, p = 0.023 and p = 0.009, respectively). We found a significantly higher mean left MPI value in the increased NT thickness group (0.574 ± 0.153) versus the normal NT thickness group (0.487 ± 0.107, p < 0.001). Within the increased NT thickness group, the mean left MPI value was similar in the fetuses with normal karyotype and those with trisomy 21 (p = 0.419). Conclusion: We demonstrated a significantly greater mean MPI value in the increased NT thickness group than in the normal NT thickness group. Within the increased NT thickness group, no differences in the left MPI value in the fetuses with normal karyotype and the fetuses with trisomy 21 were found.Öğe High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population(Cell Press, 2021) Mitani, Tadahiro; Işıkay, Sedat; Gezdirici, Alper; Yılmaz Güleç, Elif; Punetha, Jaya; Fatih, Jawid M.; Herman, Isabella; Akay, Gülşen; Du, Haowei; Calame, Daniel G.; Ayaz, Akif; Tos, Tülay; Yeşil, Gözde; Aydın, Hatip; Geçkinli, Bilgen; Elçioğlu, Nursel; Candan, Şükrü; Sezer, Özlem; Bağış Erdem, Haktan; Gül, Davut; Demiral, Emine; Elmas, Muhsin; Yesilbaş, Osman; Kılıç, Betül; Güngör, Serdal; Ceylan, Ahmet C.; Bozdoğan, Sevcan; Özalp, Özge; Çiçek, Salih; Aslan, Hüseyin; Yalçıntepe, Sinem; Topçu, Vehap; Bayram, Yavuz; Grochowski, Christopher M.; Jolly, Angad; Dawood, Moez; Duan, Ruizhi; Jhangiani, Shalini N.; Doddapaneni, Harsha; Hu, Jianhong; Muzny, Donna M.; Marafi, Dana; Çoban Akdemir, Zeynep; Karaca, Ender; Carvalho, Claudia M. B.; Gibbs, Richard A.; Posey, Jennifer E.; Lupski, James R.; Pehlivan, DavutNeurodevelopmental disorders (NDD5) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDD5 is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDD5; however, the majority of NDD5 remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDD5. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROH5) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.Öğe How to manage low estriol levels in pregnancies, one center experience(Galenos Publishing House, 2022) Yılmaz Güleç, Elif; Gezdirici, Alper; Ayaz, Akif; Öztürk, Fatma Nihal; Polat, İbrahimObjective: Low estriol (uE3) levels in the second-trimester screening for Down syndrome may be the result of fetal demise, congenital abnormalities, or some genetic hormonal disorders of the fetus. Although X-linked ichthyosis, a microdeletion syndrome with mild ichthyosis, which causes steroid sulfatase (STS) deficiency, is the most common genetic cause, second-trimester screening tests calculate the risk for a less common and severe disorder known as the Smith Lemli Opitz syndrome (SLOS). We aimed to investigate the outcomes of pregnancies with low uE3 levels in Down syndrome screening and emphasize the high prevalence of STS deficiency instead of SLOS in such cases. Methods: Fifteen pregnancies with very low uE3 levels and high risk for trisomy and/or SLOS in screening tests were evaluated and tested for STS deficiency and SLOS. Results: Seven of the pregnancies had STS microdeletion syndrome, while additional two cases were supposed to have STS gene mutation according to family and/or postnatal history. Although one fetal death was recorded, no chromosomal abnormality, SLOS, or congenital malformation was recorded in our series. Conclusions: SLOS is a very severe and rare syndrome. The risk estimation for SLOS in screening tests causes stress for pregnant women and healthcare givers. We recommend the addition of risk estimation for STS deficiency when a low uE3 level is detected in the screening test.Öğe Konjenital adrenal hiperplazi olgularımızın enzim eksikliği açısından dağılımı: Yüz kırk beş hasta ile tek merkez deneyimi(Logos Tıp Yayıncılık, 2019) Yıldız, Melek; Önal, Hasan; Aydın, Banu; Gezdirici, Alper; Akgün, Abdurrahman; Yılmaz Güleç, Elif; Belde Doğan, Beyza; Adal, ErdalAmaç: Konjenital adrenal hiperplazi (KAH), adrenal steroidogenez basamaklarından birinde gerçekleşen, enzim eksikliği nedeniyle ortaya çıkan, otozomal resesif geçişli genetik bir hastalıktır. En sık nedeni 21-hidroksilaz eksikliğidir. Bu çalışmada, bölümümüzde takipli KAH tanılı hastaların enzim eksikliği açısından dağılımlarının belirlenmesi ve klinik özelliklerinin ortaya konulması amaçlanmıştır. Yöntem: Ocak 1998-Ocak 2018 tarihleri arasında KAH tanısı alarak kliniğimizde izlenmiş olan 145 hastanın dosyası retrospektif olarak incelendi. Olguların başvuru yaşı, başvuru yakınması, cinsiyeti, izlemde puberte prekoks ve hipertansiyon gelişimi, testiküler adrenal rest tümör varlığı, hormonal değerlendirmeleri ve klinik tanıları kaydedildi. Bulgular: Çalışmaya 82 kız, 63 erkek hasta alındı. Bütün hastalar genetik cinsiyetlerine uygun yetiştirilmişti. Hastaların %87,6’sı 21-hidroksilaz eksikliği olup, bunların %80,9’u klasik (%76,3’ü tuz kaybettiren tip, %23,7’si basit virilizan tip), %19,1’i ise non-klasik (geç başlangıçlı) tip idi. Olguların %9,0’ı 11?hidroksilaz eksikliği, %2,8’i 3?-hidroksisteroid dehidrogenaz eksikliği, %0,7’si ise POR eksikliği idi. Olguların %73,8’inde akraba evliliği mevcuttu. Kız hastaların %70,7’si kuşkulu genital yapı ile erkek hastaların %73,0’ı ise tuz kaybı ile tanı almıştı. On beş hasta santral puberte prekoks nedeniyle GnRH analoğu kullanmıştı. Erkek olguların %14,3’ünde testiküler adrenal rest tümör, kız olguların %9,8’inde polikistik over sendromu mevcuttu. 11?-hidroksilaz eksikliği olgularının yaklaşık yarısında hipertansiyon mevcuttu. POR eksikliği saptanan tek hastaya sendromik özelliklerinden dolayı Antley-Bixler sendromu tanısı konulmuştu. Sonuç: Merkezimizdeki KAH hastalarında gözlenen enzim eksikliği dağılımı literatür ile uyumlu bulunmuştur. 21-hidroksilaz eksikliği açısından mutasyon saptanmayan, hipertansiyon ve sendromik görünüm benzeri klinik özellikleri bulunan ve hormonal açıdan ipucu olan hastalar nadir KAH formları açısından değerlendirilmelidir.
