Congenital combined deficiency of coagulation factors VII and X – different genetic mechanisms

Abstract

Combined coagulation factor VII (FVII) and factor X (FX) deficiency (combined FVII/FX deficiency) belongs to the group of bleeding disorders in which both factors show reduced plasma activity. It may arise from coincidental inheritance of separate coagulation factor deficiencies or a common cause as large deletions comprising both gene loci. The F7 and F10 genes are located on the long arm of chromosome 13. Here, we describe 10 cases with combined FVII/FX deficiency representing both genetic mechanisms of occurrence. Genetic analyses included direct sequencing of the F7 and F10 genes and MLPA (multiplex ligation-dependent probe amplification) for detection of heterozygous large deletions. In four patients, the combined deficiency was due to a large deletion within the terminal end of chromosome 13. In the remaining six cases the deficiency resulted from coincidental inheritance of different genetic alterations affecting both genes independently. In most cases, the genetic defects were heterozygous, presenting with prolonged PT, normal aPTT and mild or no bleeding symptoms. Only in one case compound heterozygous mutations were detected in the F10, resulting in prolonged aPTT and a more severe bleeding phenotype. To avoid a misdiagnosis of combined FVII/FX deficiency, analyses of single factor activities have to be performed in all cases with prolonged PT even if aPTT is normal. Genetic analyses are substantial for correct prediction of an inheritance pattern and a proper genetic counselling.

The EAHAD blood coagulation factor VII variant database

“…The majority of the F7 variants reported are small lesions including deletions (7.7%), duplications (1.8%), insertions (0.5%), indel rearrangements (1.8%) all smaller than 20 nucleotides with the exception of two large deletions; and single nucleotide substitutions (88.2%) with the majority of these being missense variants (74.3%; Figure 2a; http://f7-db.eahad.org/statistics.html.php). F7 is located 2.8 kb upstream of F10 and therefore large rearrangements often involve both genes leading to combined FVII and FX deficiency (Pavlova et al, 2015).…”

Inherited Moderate Factor X Deficiency Presenting as Cardiac Tamponade

“…A combined factor VII and X deficiency has been reported in the literature; however [16], this combined factor deficiency may be due to coincidental inheritance of separate coagulation factor deficiencies, such as a missense variation in both factor VII and factor X genes or a large deletion on the long arm of chromosome 13 involving both the factor VII and factor X gene. Determining the mechanism of a combined factor VII and factor X deficiency has clinical ramifications.…”

EFNB2haploinsufficiency causes a syndromic neurodevelopmental disorder

“…Few attempts have been done to correlate the phenotype of 13qter deletion with its gene content excepted for F7 and F10 genes that are implicated in combined deficiency of coagulation factors VII and X. 12 In this study, we report EFNB2 haploinsufficiency in 2 contexts, a familial 13q33.2q33.3 deletion encompassing only ARGLU1 and EFNB2 and a de novo EFNB2 pathogenic variant, and discuss its role in the phenotype of terminal 13q deletion.…”