E-ISSN: 1308-5263
Factor 8 Gene Mutation Spectrum of 270 Patients with Hemophilia A: Identification of 36 Novel Mutations [Turk J Hematol]
Turk J Hematol. 2020; 37(3): 145-153 | DOI: 10.4274/tjh.galenos.2020.2019.0262  

Factor 8 Gene Mutation Spectrum of 270 Patients with Hemophilia A: Identification of 36 Novel Mutations

Tahir Atik1, Esra Işık1, Hüseyin Onay2, Bilçağ Akgün1, Moharram Shamsali3, Kaan Kavaklo4, Melike Evim5, Gülen Tüysüz6, Namık Yaşar Özbek7, Fahri Şahin8, Zafer Salcıoğlu9, Canan Albayrak10, Yeşim Oymak11, Ekrem Ünal12, Fatma Burcu Belen13, Ebru Yılmaz Keskin14, Can Balkan4, Birol Baytan5, Alphan Küpesiz6, Vildan Culha7, Tuba Nur Tahtakesen9, Adalet Meral Güneş5, Ferda Özkınay1
1Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Genetics, İzmir, Turkey
2Ege University Faculty of Medicine, Department of Medical Genetics, İzmir, Turkey
3Ege University Institute of Health Sciences, Division of Health Bioinformatics, İzmir, Turkey
4Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, İzmir, Turkey
5Uludağ University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, Bursa, Turkey
6Akdeniz University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, Antalya, Turkey
7University of Health Sciences Turkey Ankara Pediatric Hematology Oncology Training and Research Hospital, Clinic of Pediatric Hematology, Ankara, Turkey
8Ege University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, İzmir, Turkey
9İstanbul Kanuni Sultan Süleyman Training and Research Hospital, Clinic of Pediatric Hematology and Oncology, İstanbul, Turkey
10Ondokuz Mayıs University Faculty of Medicine, Department of Pediatric Hematology and Oncology, Samsun, Turkey
11Dr. Behcet Uz Children’s Hospital, Division of Pediatric Hematology, İzmir, Turkey
12Erciyes University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, Kayseri, Turkey
13Katip Çelebi University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, İzmir, Turkey
14Süleyman Demirel University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, Isparta, Turkey

Objective: Hemophilia A (HA) is the most severe X-linked inherited bleeding disorder caused by hemizygous mutations in the factor 8 (F8) gene. The aim of this study is to determine the mutation spectrum of the F8 gene in a large HA cohort from Turkey, and then to establish a phenotype-genotype correlation.
Materials and Methods: All HA cases (270 patients) analyzed molecularly in the Ege University Pediatric Genetics Molecular Laboratory between March 2017 and March 2018 were included in this study. To identify intron 22 inversion (Inv22), intron 1 inversion (Inv1), small deletion/insertions, and point mutations, molecular analyses of F8 were performed using a sequential application of molecular techniques.
Results: The mutation detection success rate was 95.2%. Positive Inv22 was found in 106 patients (39.3%), Inv1 was found in 4 patients (1.5%), and 106 different disease-causing sequence variants were identified in 137 patients (50.6%). In 10 patients (3.7%), amplification failures involving one or more exonic regions, considered to be large intragenic deletions, were identified. Of 106 different F8 mutations, 36 were novel. The relationship between F8 genotype and inhibitor development was considered significant.
Conclusion: A high mutation detection rate was achieved via the broad molecular techniques applied in this study, including 36 novel mutations. With regard to mutation types, mutation distribution and their impact on clinical severity and inhibitor development were found to be similar to those previously reported in other hemophilia population studies.

Keywords: Hemophilia A, F8 gene, Mutation, Inhibitors, Intron 22 inversion, Turkey


Hemofili A’lı 270 Olgunun Faktör 8 Gen Mutasyon Spektrumu: 36 Yeni Mutasyon Tespiti

Tahir Atik1, Esra Işık1, Hüseyin Onay2, Bilçağ Akgün1, Moharram Shamsali3, Kaan Kavaklo4, Melike Evim5, Gülen Tüysüz6, Namık Yaşar Özbek7, Fahri Şahin8, Zafer Salcıoğlu9, Canan Albayrak10, Yeşim Oymak11, Ekrem Ünal12, Fatma Burcu Belen13, Ebru Yılmaz Keskin14, Can Balkan4, Birol Baytan5, Alphan Küpesiz6, Vildan Culha7, Tuba Nur Tahtakesen9, Adalet Meral Güneş5, Ferda Özkınay1
1Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Genetics, İzmir, Turkey
2Ege University Faculty of Medicine, Department of Medical Genetics, İzmir, Turkey
3Ege University Institute of Health Sciences, Division of Health Bioinformatics, İzmir, Turkey
4Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, İzmir, Turkey
5Uludağ University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, Bursa, Turkey
6Akdeniz University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, Antalya, Turkey
7University of Health Sciences Turkey Ankara Pediatric Hematology Oncology Training and Research Hospital, Clinic of Pediatric Hematology, Ankara, Turkey
8Ege University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, İzmir, Turkey
9İstanbul Kanuni Sultan Süleyman Training and Research Hospital, Clinic of Pediatric Hematology and Oncology, İstanbul, Turkey
10Ondokuz Mayıs University Faculty of Medicine, Department of Pediatric Hematology and Oncology, Samsun, Turkey
11Dr. Behcet Uz Children’s Hospital, Division of Pediatric Hematology, İzmir, Turkey
12Erciyes University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, Kayseri, Turkey
13Katip Çelebi University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, İzmir, Turkey
14Süleyman Demirel University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology, Isparta, Turkey

Amaç: Hemofili A (HA), faktör 8 (F8) genindeki hemizigot mutasyonların neden olduğu X’e bağlı kalıtsal kanama bozukluğudur. Bu çalışmanın amacı, Türkiye’den büyük bir HA kohortunda F8 geninin mutasyon spektrumunu belirlemek ve fenotip-genotip korelasyonu oluşturmaktır.
Gereç ve Yöntem: Mart 2017-Mart 2018 tarihleri arasında Ege Üniversitesi Pediatrik Genetik Moleküler Laboratuvarı’nda moleküler olarak analiz edilen tüm HA hastaları (270 hasta) çalışmaya dahil edildi. “İntron 22 inversiyonu” (Inv22), “intron 1 inversiyonu” (Inv1), “küçük delesyon/duplikasyonlar” ve “nokta mutasyonları” tanımlamak için F8’in moleküler analizleri, uygun bir algoritma kullanılarak gerçekleştirildi.
Bulgular: Mutasyon saptama başarı oranı %95,2’ydi. Yüz altı hastada (%39,3) Inv22 pozitif, 4 hastada (%1,5) Inv1, 137 hastada (%50,6) Yüz altı farklı hastalık yapıcı sekans varyantı saptandı. On hastada (%3,7), büyük intragenik delesyonlar olduğu öngörülen bir veya daha fazla ekzonik bölgeyi içeren amplifikasyon başarısızlığı tespit edildi. 106 farklı F8 mutasyonundan 36’sı ilk kez bu çalışmada saptandı. F8 genotipi ile inhibitör gelişimi arasındaki ilişki anlamlı kabul edildi.
Sonuç: Bu çalışmada gerçekleştirilen moleküler teknikler ile yüksek mutasyon tespit oranı elde edilmiştir; 36 yeni mutasyon saptanmıştır. Mutasyon tipleri ile ilgili olarak, mutasyon dağılımı ve bunların klinik şiddeti ve inhibitör gelişimi üzerindeki etkisi, farklı hemofili popülasyon çalışmalarında daha önce bildirilenlere benzer bulunmuştur.

Anahtar Kelimeler: Hemofili A, F8 gen, Mutasyon, İnhibitörler, İntron 22 inversiyon, Türkiye


Tahir Atik, Esra Işık, Hüseyin Onay, Bilçağ Akgün, Moharram Shamsali, Kaan Kavaklo, Melike Evim, Gülen Tüysüz, Namık Yaşar Özbek, Fahri Şahin, Zafer Salcıoğlu, Canan Albayrak, Yeşim Oymak, Ekrem Ünal, Fatma Burcu Belen, Ebru Yılmaz Keskin, Can Balkan, Birol Baytan, Alphan Küpesiz, Vildan Culha, Tuba Nur Tahtakesen, Adalet Meral Güneş, Ferda Özkınay. Factor 8 Gene Mutation Spectrum of 270 Patients with Hemophilia A: Identification of 36 Novel Mutations. Turk J Hematol. 2020; 37(3): 145-153

Corresponding Author: Tahir Atik, Türkiye


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