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

Abstract

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 Yöntemler: 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

Mutation detection and inhibitor risk in Iranian patients with Hemophilia A: Six novel mutations

“…In a study in Turkey, the examination of 270 patients with HA revealed a significant correlation between high‐risk genotypes and inhibitor formation. In our study, however, no significant difference was found between the mutation risk group and inhibitor development 33 . The lack of correlation in the present study can be attributed to the high prevalence of inhibitors in patients with splice errors, as documented in one previous study.…”

“…In our study, however, no significant difference was found between the mutation risk group and inhibitor development. 33 The lack of correlation in the present study can be attributed to the high prevalence of inhibitors in patients with splice errors, as documented in one previous study. Furthermore, missense variations are associated with an overall lower risk of inhibitor development; however, different missense Note: P-value, probability value; significance level was set at P < .05.…”

F8 gene mutation spectrum in severe hemophilia A with inhibitors: A large cohort data analysis from a single center in China

“… 12 In detail, the deleterious F8 mutations, such as large deletions or insertions and nonsense mutations destructively affect the gene structure, transcription, and translation, resulting in almost complete absence of FVIII in blood circulation, which were mostly associated with the development of inhibitors. 12 , 13 Garagiola et al 4 proposed that the F8 mutation types could be divided into high‐, medium‐, and low‐risk groups, with the above‐mentioned deleterious F8 mutations boding the highest risk of inhibitor development. The current study with the large patient cohort investigated confirmed that the high‐risk F8 gene mutation types had the highest incidence of high‐titer inhibitor and also tended to have higher peak inhibitor titer.…”

“…The immune response to FVIII replacement treatment may be due to a lack of central tolerance to FVIII protein 12 . In detail, the deleterious F8 mutations, such as large deletions or insertions and nonsense mutations destructively affect the gene structure, transcription, and translation, resulting in almost complete absence of FVIII in blood circulation, which were mostly associated with the development of inhibitors 12,13 . Garagiola et al 4 proposed that the F8 mutation types could be divided into high‐, medium‐, and low‐risk groups, with the above‐mentioned deleterious F8 mutations boding the highest risk of inhibitor development.…”

Comprehensive approach to hemophilia

“…It should be done routinely for severe to moderate hemophilia but is less frequently needed for mild hemophilia. For hemophilia B, full gene sequencing is usually done for F9, whereas inversions of intron 22 (40% frequency) and intron 1 (1%) is initially studied for severe hemophilia A (14). Since hemophilia A families with mild to moderate disease are more likely (approximately 90%) to have a point mutation, whole gene sequencing is recommended in families with mild to moderate disease if genetic testing is indicated (15).…”