Defining the molecular pathology and consequent phenotypes in Egyptian HB patients

Abstract

Background Hemophilia B (HB) (also known as Christmas disease) is a rare X-linked recessive disorder characterized by spontaneous or prolonged hemorrhages caused by mutations in Factor 9 (F9) gene leading to deficient or defective coagulation F9. Our study aimed at identifying the causative mutations within a sample of HB Egyptian patients. The present study comprised clinical data of eleven HB patients descending from six unrelated families and a seventh family including a carrier mother with a history of deceased HB sibling. Sequencing of F9 gene was performed. Results The study revealed four mutations; two missense NM_000133.3:c.676C>G, (P.Arg226Gly) and NM_000133.3:c.1305T>G, (p.Cys435Trp), and two nonsense mutations NM_000133.3:c.880C>T, (p.Arg294*) and NM_000133.3:c.1150C>T, (p.Arg384*), identified mutations spanned exons 6 and 8 of which a total of three mutations are located in hotspot exon 8 of F9 gene. Conclusions Reviewing the literature, this is the first molecular analysis of F9 gene in HB Egyptian patients. Consistent genotype/phenotypic severity correlation could be concluded, helping proper genetic counseling and prenatal decision taking.

Genotype Hemophilia Screening Program Identified 2 Novel Variants Including a Novel Variant (c.5816-2A > G) Causing a Pathogenic Variant of the Factor 8 Gene

“…In line with literature reports, the present study confirms the well-known frequent genetic defect of HA and HB, where the null allele (large deletion, insertion/deletion mutations, nonsense, and gene rearrangements principally inversion of intron 22) was responsible for the most frequent genetic abnormalities in severe HA (10 out of 26 severe forms, 38.4%), whereas missense mutations have been found in the majority of patients with moderate (3 out of 5, 60%) and mild forms of the disease (5 out of 7, 71.4%) and comprise the most frequent molecular defect in HB (>50% of all reported mutations) (Supplemental Tables 1 and 2, online version). 7,17,19,20,22,23 Our study also in agreement with previously published data 3,24 found that the risk of developing inhibitors was much less frequent in HB patients compared to HA (5.1% vs 25%, respectively), and the risk was allied mostly in severely affected patients except for 2 mild HA cases (Supplemental Tables 1 and 2, online version), thus supporting the assumption that the higher prevalence of the less severe missense mutations in HB compared to HA provides a potential biological reason for explaining the milder disease phenotype regarding bleeding severity and inhibitor risk in HB versus HA. 3 It is well known that the risk for inhibitor development to factor replacement therapy is related to several factors including the type and location of genetic defect, where variants with gross defects, such as Out of all cases, 1 case was positive for the factor inhibitors.…”

“…In line with literature reports, the present study confirms the well-known frequent genetic defect of HA and HB, where the null allele (large deletion, insertion/deletion mutations, nonsense, and gene rearrangements principally inversion of intron 22) was responsible for the most frequent genetic abnormalities in severe HA (10 out of 26 severe forms, 38.4%), whereas missense mutations have been found in the majority of patients with moderate (3 out of 5, 60%) and mild forms of the disease (5 out of 7, 71.4%) and comprise the most frequent molecular defect in HB (>50% of all reported mutations) ( Supplemental Tables 1 and 2 , online version). 7 , 17 , 19 , 20 , 22 , 23 …”