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Copy Number Variation Analysis in Turkish Patients with Congenital Bilateral Absence of Vas Deferens

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Copy Number Variation Analysis in Turkish Patients with Congenital Bilateral Absence of Vas Deferens RESEARCH ARTICLE Acta Medica Alanya 2021;5(2): 181-189 ARAŞTIRMA DOI:10.30565/medalanya.966940 Copy Number Variation Analysis in Turkish Patients with Congenital Bilateral Absence of Vas Deferens Konjenital Bilateral Vas Deferens Yokluğu Olan Türk Hastalarda Genomik Kopya Sayısı Varyasyonları Analizi Durkadin Demir Eksi1*, Elanur Yilmaz², Yigit Akin3, Mustafa Faruk Usta4, Mehmet Murad Basar5, Semra Kahraman⁶, Munire Erman⁷, Ozgul M Alper⁸ 1. Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Medical Biology, Antalya, Turkey 2. Koç University, Research Center of Translational Medicine İstanbul, Turkey 3. İzmir Katip Çelebi University, Faculty of Medicine, Department of Urology, İzmir, Turkey 4. Akdeniz University, Faculty of Medicine, Department of Urology, Antalya, Turkey 5. Memorial Şişli Hospital, Department of Urology, İstanbul, Turkey 6. Memorial Şişli Hospital, Department of Gynecology and Obstetrics, İstanbul, Turkey 7. Akdeniz University, Faculty of Medicine, Department of Gynecology and Obstetrics, Antalya, Turkey 8. Akdeniz University, Faculty of Medicine, Department of Medical Biology and Genetics, Antalya, Turkey ABSTRACT ÖZ Objective: Congenital Bilateral Absence of the Vas Deferens (CBAVD) is a Amaç: Konjenital Bilateral Vas Deferens Yokluğu (CBAVD), erkeklerde infertiliteye developmental abnormality that causes infertility in males. According to the yol açan gelişimsel bir anomalidir. Literatüre göre CBAVD’li olguların %88’e kadarı en literature, up to 88% of CBAVD cases have at least one pathogenic Cystic Fibrosis az bir Kistik Fibrozis Transmembran Regülatör geni (CFTR) mutasyonuna sahiptir. Transmembrane Conductance Regulator gene (CFTR) mutation. However, based on Ancak, daha önceki verilerimize göre CBAVD’li Türk hastalarda bu oran %15.90’dır. our previous data, this rate was 15.90% in Turkish patients with CBAVD. We aimed Çalışmamız kapsamında Türk popülasyonundaki CBAVD ile ilişkili olabilecek to identify genomic copy number variations (CNV) and candidate genomic regions genomik kopya sayısı varyasyonları (CNV) ve aday genomik bölgelerin tanımlanması which could related to the CBAVD in Turkish population. amaçlanmıştır. Methods: CNV analysis was performed in 19 Turkish CBAVD patients normal Yöntemler: Normal karyotipe ve yabanıl tip CFTR genotipine sahip 19 Türk CBAVD’li karyotypes and a wild type CFTR genotype. We suggested that the DAD1 gene may hastanın CNV analizi gerçekleştirildi. CNV bulgularımızın analizi ve veritabanlarının be a candidate gene related to CBAVD by reviewing online databases and analyzing taranması ile DAD1 geni CBAVD ile ilişkili olabilecek potansiyel aday gen olarak CNV findings. Sanger sequencing of the DAD1 gene exons was performed in 22 tanımlandı. 22 CBAVD’li hastada da DAD1 geni ekzonlarının dizi analizi Sanger patients. dizileme metoduyla yapıldı. Results: We identified 11 CNVs that most likely related with the disease in nine of Bulgular: 19 hastanın dokuzunda (%47.3) hastalıkla ilişkili olabilecek 11 adet 19 (47.3%) patients. As the most common CNV, 14q11.2 deletions were detected in CNV saptandı. En sık saptanan CNV olarak 14q11.2 delesyonu, hastaların üçünde there (15.79%) of the patients. There was only DAD1 gene in the sharing genomic (%15.79) belirlendi. 14q11.2 delesyonlarından ikisinin ortak varyant bölgesinde region of two of the 14q11.2 deletions. No sequence variation was detected in the yalnızca DAD1 geni lokalize idi. Dizi analizi ile, hastaların DAD1 geninde herhangi DAD1 gene of the patients. bir dizi varyasyonu saptanmadı. Conclusion: The 14q11.2 chromosomal region and the DAD1 gene may be Sonuç: 14q11.2 kromozomal bölgesi ve DAD1 geni CBAVD ile ilişkili olabilir. associated with CBAVD. Further studies are needed to indentify the contribution of CNVlerin ve DAD1 geninin CBAVD etiyolojisine katkısını tanımlamak için ileri CNVs and DAD1 gene to CBAVD etiology. çalışmalar gerekmektedir. Keywords: copy number variations; CBAVD; male infertility; DAD1 Anahtar Kelimeler: kopya sayısı varyasyonları; CBAVD; erkek infertilitesi, DAD1 Received: 10.07.2021 Accepted: : 01.08.2021 Published (Online): 30.08.2021 *Coresponding Author: Durkadin Demir Eksi, Asst. Professor, Ph.D. Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Medical Biology, Kestel Campus Alanya, Antalya, Turkey 07425. Phone: +90 242 510 6060 / 3570 Fax: +90 242 510 6009 E-mail: [email protected]. ORCID: 0000-0002-5887-3141. To cited: Demir Eksi D, Yilmaz E, Akin Y, Usta MF, Basar MM, Kahraman S, Erman M, Alper OM. Copy Number Variation Analysis in Turkish Patients with Congenital Bilateral Absence of Vas Deferens. Acta Med. Alanya 2021;5(2): 181-189 doi:10.30565/medalanya.966940 Acta Medica Alanya MAY- AUG 2021 Open Access http://dergipark.gov.tr/medalanya. 181 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License. Demir Eksi D. et al. CNV Analysis in Patients with CBAVD INTRODUCTION gene fusion, position effect and other effects on gene function [13]. To date, CNV analyses s a global health problem, infertility affects for idiopathic azoospermia from different ethnic approximately 8-12% of all couples [1]. It has A backgrounds or populations have been performed been estimated that 40-50% of all infertility cases is in several studies [14, 15]. We hypothesise that due to ‘male factor’ infertility and affects about 7% CNVs might explain, at least partially, the unknown of all men [1]. Congenital structural anomalies of the genetic etiology of CBAVD. Therefore, we aimed male genital tract are contributing factors in male to identify the possible candidate genomic infertility. Numerical or structural chromosomal regions and genes which could cause CBAVD in abnormalities, Y chromosome microdeletions, Turkish patients not carrying CFTR mutations by and Cystic Fibrosis Transmembrane Conductance performing whole genome CNV analysis. Here, we Regulator (CFTR, NM_000492.3) gene mutations report that Defender Against Cell Death 1 (DAD1) associated with congenital bilateral absence of localized at 14q11.2 in our cohort is a gene that vas deferens (CBAVD, OMIM 277180) are the may need to be investigated further in association most common genetic reasons of male infertility with CBAVD. DAD1 is known to be a negative [2]. CBAVD accounts for 1-2% of all male infertility, regulator of apoptosis [16]. which is a condition characterized by the blockade of the transportation of the spermatozoa from MATERIALS AND METHODS testicular or epididymal structures to the distal genital tract, resulting in azoospermia [3]. 88% Ethical approval and patients of Caucasian, 78% of Non-Caucasian patients This clinico-genetic study was conducted with with CBAVD carry at least one CFTR mutation the collaboration of Akdeniz University Faculty of [4]. However, CFTR mutations were found to be Medicine, Izmir Katip Celebi University Faculty of less common in Turkish CBAVD patients [5-7]. We Medicine, and Istanbul Sisli Memorial Hospital, previously reported that only 15.90% had CFTR Turkey. The study protocol was approved by mutations [7]. The lower frequency of CFTR the Akdeniz University Clinical Research Ethics mutations among Turkish CBAVD cases, as well Committee (approval No: 2014-# 383) under as differential mutation profiles, demonstrated the the recent version of the Helsinki Declaration. impact of geographical and ethnic backgrounds on Informed consent was obtained from all subjects CBAVD etiology [5, 7]. Besides CFTR, ADGRG2 when they were enrolled in the study. (Adhesion G protein-Coupled Receptor G2) gene variants were identified as a cause of CBAVD The patients who applied to the urology outpatient with a prevalence of 7.4% and 20% in French and clinic due to primary infertility were evaluated. Chinese cases, respectively [8, 9]. Recently, it was All of the patients had not used any birth control shown that, heterozygous SLC9A3 deletions were method for at least one year, they had no sexual found in 37.9% of the Taiwanese patients, and dysfunction and no comorbidity. Twenty-two SCNN1B and CA12 genes regulating CFTR protein unrelated, adult Anatolia-originated Caucasian levels were found to be associated with CBAVD males with CBAVD were included in the study. All in some patients without CFTR mutations [10, 11]. patients were azoospermic. CBAVD patients were Nevertheless, these gene variations explain the determined by using physical examination, scrotal, disease in only a limited fraction of all CBAVD transrectal ultrasound (USG), semen analysis, patients. The genetic structure of the present day and biochemical tests. CBAVD cases with wild- Turkish people may not be similar with Europeans type CFTR genotype, normal karyotype, without a or Asians because of migrations from different Y chromosome microdeletion were included in this geographical areas [12]. We hypothesized novel study. Renal aplasia was excluded by pelvic USG. genes and/or genomic regions may be related to idiopathic CBAVD in Turkish people. Copy Number Variation Analysis Genomic copy number variations (CNVs) can For molecular genetic analyses, patients’ genomic lead to disease by various molecular mechanisms DNA was isolated from peripheral blood by using including gene dosage effect, gene disruption, a non-enzymatic method modified from Lahiri and Acta Medica Alanya 2021:5:2 182 Demir Eksi D. et al. CNV Analysis in Patients with CBAVD Nurnberger [17]. The quality of DNA samples was for CBAVD. The gene with a possible role in the tested by agarose gel
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