Summary

To investigate the relationship between clinical phenotype, clottingactivity (FVIIc) and FVII genotype, a multi-center study offactor VII (FVII) congenital deficiency with centralized genotypingand specific functional assays was carried out. FVII mutationscharacterized in patients (n=313) were extremely heterogeneous(103 different, 22 novel). Clinical phenotypes ranged fromasymptomatic condition, including 15 homozygotes and 14double heterozygotes, to patients with a severe disease characterizedby life-threatening and disabling symptoms (CNS, GIbleeding and hemarthrosis) strongly associated with an early ageof presentation. Based on type and number of symptoms weclassified 90 'severe' (median FVIIc 1.4%, IQR [InterquartileRange] 0.9-3.8), 83 'moderate' (FVIIc 3%, IQR 1-21.7), and 140'mild' bleeders (FVIIc 14%, IQR 3-31).The significantly differentFVIIc levels, and the decreasing prevalence of homozygotes or double heterozygotes among severe (98%),moderate (84%) andmild (56%) bleeders, further support our classification.The excessof females among moderate bleeders (female/male ratio=2.6) is attributable to menorrhagia.There was no evidence formodulation of clinical features by frequent functional polymorphisms.Homozygotes for the same mutation (Ala294Val;11125delC) with similar FVIIc and FXa generation levels,showed striking differences in clinical phenotypes.Our study depictsthe ample clinical picture of this rare disorder, proposes aseverity classification and provides arguments for the early managementof the disease in the severe cases. Genotype-phenotyperelationships indicate the presence of major environmentaland/or extragenic components modulating expressivity ofFVII deficiency.