Haemophilia A is a common X-linked recessive disorder caused by mutations in F8 leading to deficiency or dysfunction of coagulant factor VIII (FVIII). Despite tremendous improvements in mutation screening methods, in a small group of patients with FVIII deficiency suffering from haemophilia A, no DNA change can be found. In these patients, analysis reveals no causal mutations even after sequencing the whole coding region of F8 including the flanking splice sites, as well as the promoter and the 3' untranslated region (UTR). After excluding the mutations mimicking the haemophilia A phenotype in interacting partners of the FVIII protein affecting the half life and transport of the protein, mutations or rearrangements in non-coding regions of F8 have to be considered responsible for the haemophilia A phenotype. In this review, we present the experiences with molecular diagnosis of such cases and approaches to be applied for mutation negative patients.
Keywords: Haemophilia A; extended diagnostic flowchart; mutation negative patients.