What is the F8 gene duplication (FVIII Padua)?

Answer: A 23.4-kb tandem duplication of the proximal F8 gene reported in 2 Italian families. It is the first thrombophilic defect described in F8, designated FVIII Padua.

• Phenotype: severe thrombophilia with extreme, persistently elevated FVIII (antigen and activity >400%) as the only thrombophilic defect. The proband had recurrent VTE before age 50.
• Genetics: the duplication cosegregated with high FVIII levels and was absent in 103 normal controls. Targeted screening of 50 unrelated VTE patients with FVIII ≥250% found a second family carrying the same rearrangement on the same genetic background suggesting a founder effect.
• Mechanism: carriers show ≥2-fold upregulation of F8 mRNA, consistent with open chromatin signatures and enhancer elements inside the duplicated region.

Related — do not confuse with FIX-Padua. Same eponym, unrelated entity: FVIII Padua is an F8 duplication causing thrombophilia via overexpression; FIX-Padua is a hyperfunctional F9 point variant deliberately used in hemophilia B gene therapy.

Source: Partial F8 gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia. Blood. 2021;137(17):2383 — primary-literature