Clinical correlates among 49 families with hemophilia A and factor VIII gene inversions

Abstract

Inversions between a gene A copy within intron 22 of the factor Vlll gene and additlonal copies outside the factor Vlll gene were found In 49 families with hemophilia A. Inversion patterns were that of recombination with a distal gene A copy in 34, a proximal copy In 14, and a third (variant) copy in one. Baseline factor Vlll clotting activity levels were 1 1 % of normal in 43 and 1% in 6. No inversion was detected in 61 other families whose affected members had 51% activity levels nor in 42 familles with moderately severe hemophllia A and 2-5% baseline levels. Both high titer and low level alloantibody lnhibltors were found in patients with or without an inversion. Of 13 high titer inhlbltors, 8 were perslstent and 1 of these patients had an inversion. Of 5 that responded to daily factor Vlll infusions, 4 were in patients with gene inversions. Of the 49 families with an inversion, the occurrence of hemophilla was Isolated in 30 and the mother was a carrier in the 25 In which addltlonal family members were informatlve. In three of these families with Isolated occurrence, the maternal grandmother was a carrier whereas in three others a de now mutatlon occurred in the maternal grandfather's factor Vlll gene. Screening for gene Inversions in patlents with severe (or "borderline" severe) hemo-philia A provides a direct marker of the mutation in 45% of families. It is useful even If there is no living affected member and In predicting the likely severity of an infant in which there are no reliable baseline clotting activities, including 70% of families with isolated occurrences of hemophilia A.

Factor VIII gene inversions and polymorphisms in Brazilian patients with haemophilia A: carrier detection and prenatal diagnosis

“…[34] observed atypical hybridization patterns of inversion and described the first detailed analysis; the abnormal result was found to be caused by an inversion involving an extra copy of intron 22 from a site only 70–200 kb telomeric of the FVIII gene. Although other variant band patterns of inversions have been described [18,25,28,32], we did not observe any unusual rearrangements in our patients.…”

“…Naylor et al [34] observed atypical hybridization patterns of inversion and described the ®rst detailed analysis; the abnormal result was found to be caused by an inversion involving an extra copy of intron 22 from a site only 70±200 kb telomeric of the FVIII gene. Although other variant band patterns of inversions have been described [18,25,28,32], we did not observe any unusual rearrangements in our patients. Interestingly, we observed in a single female patient (not included in the study, mother of a patient with severe haemophilia A) the mild form of the disease, but her band pattern was that of a carrier of distal inversion.…”

A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins

“…DNA samples were from 188 unrelated families (64 clinically severe) including patients or obligate carriers with haemophilia A not previously described. The 64 with severe haemophilia A had screened negatively for gene inversions, recurrent Arg to Stop codons, and gross deletions; thus the series did not include 67 families with factor VIII gene inversions ( Weinmann et al , 1996 ; Liu & Thompson, 1999), nine with CGA (Arg) to TGA (stop) mutations, four with CG missense mutations ( Reiner & Thompson, 1992; Reiner et al , 1992 ) or two with partial gene deletions. Samples were submitted for clinical carrier testing or obtained following informed consent under a protocol approved by the University of Washington's Human Subjects Review Committee (IRB).…”

Consequences of factor IX mutations in 26 families with haemophilia B

“…Samples were drawn for clinical carrier testing or an approved research protocol with informed consent. Plasma factor IX assays, DNA preparation, amplification primers, and restriction digests were as described (Thompson & Chen, 1993;Weinmann et al, 1996;Chen et al, 1995). DNA sequencing was performed in both directions using an Applied Biosystems automated sequencer, model 373.…”