A NOVEL DNA INVERSION CAUSING SEVERE HEMOPHILIA-A

Almost half of all cases of severe hemophilia A are caused by recurren t DNA inversions, which disrupt the factor VIII (FVIII) gene. These in versions generally occur between a region of intron 22 (int22h) and on e of two homologous copies of this region, located 300 to 400 kb telom eric to the FVIII gene. They are routinely detected by a Bcl I Souther n blot assay in which the sizes of two of the three normal hybridizati on bands are characteristically altered. However, atypical hybridizati on patterns have been observed, and this report describes the first de tailed analysis of a hemophilia A patient with such a pattern. The abn ormal result was found to be caused by a novel FVIII inversion involvi ng an extra copy of int22h from a site only 70 to 200 kb telomeric of the FVIII gene. Polymerase chain reaction (PCR) allowed one of the inv ersion junctions to be analyzed, showing that the int22h sequence at t his inversion junction was truncated. This patient and his novel inver sion provide further evidence that int22h is associated with instabili ty in Xq28. (C) 1996 by The American Society of Hematology.