Severe factor VII deficiency with recurrent intracranial haemorrhages owing to double heterozygosity for a splice site mutation of an IVS4 and a novel nonsense mutation in exon 8 (Gln211→Term)

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Abstract
Genetic analysis of a 10‐month‐old Japanese baby boy with recurrent intrathoracic bleeding, cerebral haemorrhages and gastrointestinal bleeding secondary to severe factor VII (FVII) deficiency revealed evidence of two distinct mutations of FVII: a splice site mutation of G→A at nucleotide 6071 in the IVS4 splice site and a novel nonsense mutation (Gln211→Term) in exon 8. His bleeding was difficult to control without prophylactic infusion of FVII. We detected a heterozygous splice site mutation of the IVS4 in his mother and a heterozygous nonsense mutation in exon 8 (Gln211→Term) in his father. The parents' FVII levels are both 50% of normal controls. The FVII:C in plasma from the proband was < 1·5% of normal controls. FVII:antigen (Ag) was < 1% of normal controls, using a monoclonal antibody (mAb) hVII‐B101/1 that specifically reacts with FVII epidermal growth factor 1 (EGF‐1), and 5% of normal controls, using a rabbit polyclonal antibody against human FVII. After immunoadsorption with mAb hVII‐B101/B1–Sepharose 4B, FVII levels of both the proband and his mother were 5% of normal controls; after immunoadsorption the FVII levels of normal subjects were < 1%. We hypothesize that secretion of a small amount of dysfunctional FVII lacking EGF‐1 into the circulation accounts for this observation.