Mutation Spectrum and Genotype–Phenotype Analyses in a Pakistani Cohort With Hemophilia B

Abstract

This study aimed to (1) identify F9 genetic alterations in patients with hemophilia B (HB) of Pakistani origin and (2) determine the genotype-phenotype relationships in these patients. Diagnosed cases of HB were identified through registries at designated tertiary health-care centers across the country. Consenting patients were enrolled into the study. The factor IX (FIX) coagulation activity (FIX:C) and key clinical features were recorded. Direct sequencing of F9 was carried out in all patients. All the variants identified were analyzed for functional consequences employing in silico analysis tools. Accession numbers from National Center of Biotechnology Information ClinVar database were retrieved for the novel variants. Genotype-FIX:C relationships were determined followed by FIX:C clinical phenotype assessment. A total of 52 patients with HB from 36 unrelated families were identified, which mainly comprised patients with moderate HB (n ¼ 35; 67.3%). Among these, 35 patients from 22 unrelated families could be contacted and enrolled into the study. Missense variants were the most frequent (58.8%), followed by nonsense variants (17.6%). A missense, a short insertion, and a nonsense novel variants in exon 2, 6, and 7, respectively, were also identified. The disease manifested FIX:C heterogeneity in relation to the corresponding mutation in a significant number of cases. Clinical phenotype heterogeneity was also observed in relation to FIX:C-based severity assessment. We concluded that the registered FIX-deficient population of Pakistan mainly comprises moderate HB. F9 mutation spectrum in Pakistani patients with HB is heterogeneous. The HB population of Pakistan manifests a significant amount of genotype-FIX:C and FIX:C-clinical phenotype heterogeneities.

Turkey Experience in Molecular Analysis of Hemophilia B: F9 Gene Mutation Spectrum and Genotype-Phenotype Correlation

“…Son 20 yılda birçok farklı toplumda, HB olgularında F9 geninde varyant dağılımını bildiren çok sayıda araştırma gerçekleştirilmiştir. [15][16][17] Rydz ve ark. 2013 yılında Kanada referans genotiplendirme laboratuvarın sonuçlarını sunmuşlardır.…”

“…ise 36 aileden 52 HB olgusunu F9 dizi analizi ile değerlendirmiş ve 21 aileden 34 olguda 17 farklı varyant bildirmişlerdir. 15 Bu konuda ülkemizde yapılan çalışmalar incelendiğinde, Onay ve ark. 34 HB olgusunun tamamında ve Çilingir ve ark.…”

“…Çalışma grubunda saptanan yeni mutasyonların moleküler özellikleri ve ilişkili oldukları hastalık fenotipleri. farklı klinik tablolara yol açabileceği bilinmektedir 15. Bu durum klinik fenotipin ortaya çıkmasında varyant tipinden başka faktörlerin de (çevresel, epigenetik veya modifiye edici genler) etkili olabileceğini düşündürmektedir.…”

Genotype-Phenotype Heterogeneity in Haemophilia

“…This is, however, noteworthy that patients with a specific severity of the disease do not always behave as anticipated. Studies have reported a significant number of severe haemophilia cases with a milder phenotype [1,12,13]. In such cases, bleeding phenotype resembles that of moderate severity.…”

“…Repeat variants are not yet reported to associate with the disease. In majority of the cases, specific mutations result in the same disease severity, a phenomenon referred to as genotype-phenotype correlation [13,15].…”