F8 and F9 mutations fail to co‐segregate in a family with co‐incident haemophilia A and B

Abstract

Haemophilia A and B in one individual may arise from co-incident inheritance of independent mutations in the F8 and F9 genes. However, this association is rare and has been studied poorly at a genetic level. We report a male patient with abnormal bleeding and reduced factor VIII:C (26 IU dL(-1)) and factor IX:C (35 IU dL(-1)). This index case harboured a F8 c.979C>G transversion (predictive of p.Leu327Val) and a F9 c.845A>G transition (predictive of p.His282Arg) which have been previously associated with mild haemophilia A and B, respectively. Identical F8 and F9 mutations were identified in the mother and maternal grandmother. However, an affected maternal uncle showed only the F8 c.979C>G mutation, indicating haemophilia A alone. The sister of the index case was heterozygous only for F9 c.845A>G, indicating carriership of haemophilia B alone. The non-Mendelian inheritance of F8 c.979C>G and F9 c.845A>G in this kindred is consistent with recombination between F8 and F9 and illustrates the large recombination distance between these loci. Recognition of this phenomenon was essential for accurate genetic counselling in this kindred.

A de novo factor VIII mutation in a haemophilia B family leading to combined deficiency of factor VIII and IX

“…arthrodesis or arthroplasty. [1][2][3] However, most patients with haemophilia are younger than patients with osteoarthritis or rheumatoid arthritis.…”

“…A de novo factor VIII mutation in a haemophilia B family leading to combined deficiency of factor VIII and IX Familial multiple coagulation factor deficiency (FMCFD) is a rare bleeding disorder, characterized by deficiency of more than one coagulation factor in the same individual. They occur either due to a coincidental inheritance of both the deficiencies [1][2][3][4] or due to a common molecular event for instance, a deletion involving parts of both the genes specifically in cases where the two genes are not far apart. 5 They can also occur in association with the commonest bleeding disorder, von Willebrand disease.…”

The odds and implications of coinheritance of hemophilia A and B

“…Congenital hemophilia A (HA) and B (HB) are rare X‐linked recessive disorders, occurring in approximately 1 in 5000 and 1 in 30 000 live male births, respectively 1 . Combined inheritance of HA and HB is even more rare, but has been reported due to inheritance of 1 variant from each parent 2 or due to 2 variants from a single parent 3‐6 . We report 2 families with pathogenic genetic variants for HA and HB and evaluate how the variant F8 and F9 alleles were inherited within the families.…”