MOLECULAR INCIDENCE OF FVIII GENE INVERSIONS IN ARGENTINE FAMILIES WITH SEVERE HAEMOPHILIA A.

CARLOS DE BRASI, MIGUEL CANDELA, MÓNICA CERMELJ, IRMA SLAVUTSKY, IRENE LARRIPA, RAÚL PEREZ BIANCO, MIGUEL DE TEZANOS PINTO.

La Haya, Holanda

Congreso; XXIII International Congress of the Word Federation of Hemophilia (WFH).; 1998

WFH

Hemophilia is a heritable sex linked clotting disorder which affects 1:5000 males in all human populations. Hemophilia A ,  characterized by a low clotting activity of FVIII:C in plasma, can be classified in severe (SHA) (FVIII:C<1%) and moderate-mild (1-25%). FVIII gene changes involved in SHA show approximately half of the patients with different mutations, including missense, nonsense, frameshift, deletions, and in the remaining half of the patients, the  intron 22 FVIII gene inversions (Inv22). This rearrangements dislocates the first 22 (of 26) exons of the factor VIII gene, preventing the formation of a full length transcript and leading to severe haemophilia A without detectable circulating factor VIII protein. The inversions are recognized by disctintive patterns of BclI-digested genomic DNA on Southern blots, hybridized with gene F8A probe. This methodology allows us to differentiate the bands pattern corresponding to the Inv22 type I or distal, Inv22 type II or proximal and without Inv22 or normal. Twenty-two Argentine families with SHA have been studied (including 62 members: 25 probands, 19 mothers and 18 female relatives). It has been found 11 families (50%) with the Inv22, 10 (45%) with the Inv22 type I and 1 (5%) with the Inv22 type II. Except for the low incidence founded in type II inversion (regarding the expected 9-10% of SHA), probably due to the small number of studied families;  our findings are closely linked to previous published data (Blood 86:2206-2212, 1995). The identification of such a frequent mutation in our population of SHA patients can be applied to carrier and prenatal diagnosis considerably improving the provision of genetic counselling in families with the disease.