Genetic analysis of a hemophilia B family with a novel F9 gene mutation

Abstract

At present, there are no effective methods for the treatment of hemophilia B, and it has high mortality and disability. Therefore, it is very important for the carriers to carry out genetic counseling and make prenatal diagnosis. In this study, we made gene and prenatal diagnoses in a family with a novel F9 gene mutation, and report a novel F9 gene mutation. All exon sequences and flanking sequences of F9 gene were analyzed by Sanger sequencing in the proband; and then according to the F9 gene mutation in the proband, the F9 gene sequencing was performed on the family members. Based on the above results, the pathogenic mutation in F9 gene was finally identified, which was used for prenatal diagnosis. Sanger sequencing revealed c.1232G>C [p.Ser411Thr] mutation in F9 gene in the proband. c.1232G>C heterozygous mutation was also found in the proband's mother and grandmother, but male family members without hemophilia B had no this mutation. The analyses of amniotic fluid samples indicated positive sex-determining region on Y chromosome ( SRY ), and no c.1232G>C [p.Ser411Thr] mutation in F9 gene. We identified a pathogenic mutation in F9 gene in the family, made a prenatal diagnosis for the female carrier and reported a novel F9 gene mutation.

Defining the molecular pathology and consequent phenotypes in Egyptian HB patients

“…Mutational screening of F9 gene in eleven clinically diagnosed Egyptian hemophilia-B patients and carrier mothers revealed four point mutations including two missense and two nonsense mutations that were correlating with phenotypic severity within the studied patients. Up to November 2018, the F9 gene mutation database (EAHD Coagulation Factor Variant Databases) has recorded a total of 1094 mutations in 3713 HB patients [7], more than 3940 unique mutations have been reported so far in HGMD, 2020 [6]; point mutations accounts for 73.1% and mutations within the serine protease domain (SPD) account for about 56.1% among different populations [5,[8][9][10][11][12][13][14][15][16][17]. In agreement with that, all the detected mutations within our studied cohort were point mutations, three out of four detected mutations are within the protease domain, the greater part of codons (280-451) coded by the largest exon in the F9 gene (exon 8).…”

“…We identified one missense mutation (NM_000133.3: c.676C>G; NP_000124.1: p.Arg226Gly) located in exon 6 in two HB patients (patients 1 and 2) who clinically presented with moderate phenotype. However, severe and moderate forms of the disease resulting from this mutation have been reported earlier in different populations like China, Turkey, and France [18][19][20]; this might be attributed to different ethnic backgrounds [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21].…”

“…Currently, the multiplex ligation dependent probe amplification (MLPA) method is used to detect large deletion or duplication mutations in F9 gene, however, it cannot detect point mutations that are considered as the major type of causative mutations in HB [ 8 ], and our studied patients were all diagnosed through direct sequencing of all coding exons of the F9 gene.…”

Current therapeutic approaches in the management of hemophilia—a consensus view by the Romanian Society of Hematology

“…PCR is used for common variants (32) and sequencing for rare variants. The F9 gene sequencing can be performed through Sanger sequencing (33) or next generation sequencing (NGS) technologies (34). Genetic counseling for prospective parents before conception is important.…”

Hemofilia B o enfermedad de Christmas

“…Las mutaciones en el gen F9 impiden la producción de factor IX, lo cual conduce a los síntomas asociados con la hemofilia [19,20]. Se ha encontrado gran variabilidad en las mutaciones del gen F9, incluyendo mutaciones puntuales, deleciones, inserciones, cambios complejos y polimorfismos neutrales, entre otros defectos.…”