Severe FVII deficiency caused by a new point mutation combined with a previously undetected gene deletion

Abstract

SummaryA 3-week-old Caucasian female presented with severe unprovoked parenchymal cerebral haemorrhage. Her plasma factor VII (FVII) activity was <0AE01 units/ml. FVII activities for her mother and sister were 0AE65 units/ ml and 0AE51 units/ml, respectively, while her father's level was normal. These results indicated that the mother was heterozygous for a non-functional F7 gene that had also been inherited by the proband's sister. The proband's severe FVII deficiency was caused by a new mutation in her paternal F7 gene coupled with the inheritance of the non-functional maternal F7 gene. DNA sequence analysis revealed that the proband had apparent homozygosity for a novel single point mutation (g.3907G > A) changing the codon for Glu29 to Lys (E29K); neither parent had the E29K mutation. Because of the unlikelihood that the proband was homozygous for two identical new point mutations, the DNA sequence abnormality was more likely to have arisen from a single mutated gene on one allele and a F7 gene deletion on the other allele. Real time polymerase chain reaction (PCR) analysis confirmed that the proband had inherited a gene deletion that was present in the maternal side of the family. Subsequent clotting assays and real time PCR revealed that the maternal deletion also included the closely linked F10 gene.

Severe prothrombin deficiency caused by prothrombin‐Edmonton (R‐4Q) combined with a previously undetected deletion

“…Real‐time PCR was carried out on the DNA Engine Opticon 2 Real‐Time PCR Detection System (Bio‐Rad Laboratories) using the following cycling parameters: 94 °C for 2 min, 40 cycles of 95 °C for 15 s and 60 °C for 1 min. Post‐PCR analysis was carried out as described [16].…”

Phenotype and genotype report on homozygous and heterozygous patients with congenital factor X deficiency

“…Two previously reported mutations on F7 and FIX gene (F9), the p.Glu69Lys in FVII and the p.Glu70Lys in FIX caused severe FVII deficiency and severe hemophilia B, respectively. 19,20 These two mutations were originally reported as Glu29Lys in FVII and Glu30Lys in F9. The second novel mutation was p.Asp103His, identified in patient R432, a 19 year old woman, consisting of a G to C transversion (c.307G>C) in exon 4 encoding the EGF1 domain.…”

Severe FX deficiency caused by a previously unidentified 4‐bp deletion compound heterozygous with a large deletion involving FVII and FX genes

“…Deletions have also been associated with a severe bleeding phenotype. [5,6]. We here present the first characterization of a patient with severe FX deficiency due to the novel mutation c.162_165delAAGA and a co‐existent large deletion involving both FVII and FX genes.…”

“…It is associated with severe, predominantly mucosal haemorrhaging following minimal trauma (including purpura, petechiae and bruising; epistaxis, gingival bleeding, severe menorrhagia and rarely haemarthroses) [1]. Diagnosis can be made by flow cytometry using IIb/ IIIa antibodies or by formal platelet aggregometry which will show absent aggregation with all agonists apart from ristocetin [2] [6].…”