The Malmö International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A.
OBJECTIVE
The strongest risk factor identified for inhibitor development in people with severe hemophilia A is the type of factor VIII gene mutation. The objective of this study was to evaluate the mutation type dependent concordance rate of inhibitor formation in siblings.


METHODS
The gene defect, treatment and inhibitor history were evaluated in 113 families in which two or more siblings had severe hemophilia A.


RESULTS
Seventy-nine of the families (69.9%) were concordant in that either all or none of the siblings had a history of inhibitors. The concordance in 59 families with inhibitors was 42.4%. The corresponding figures for the 74 families with intron 22 inversion were 63.5% and 40.0%, respectively, and the overall concordance within 14 families with nonsense mutations was 78.6%. The siblings in two families with large gene deletions had no inhibitor history. A small proportion of the families with missense mutations, small deletions/insertions and splice site mutations developed inhibitors, but in four of the families two or more siblings developed high-responding inhibitors. In 18 of the 25 concordant families (72.0%) with inhibitors, the inhibitor was also of the same type (high-responding).


CONCLUSIONS
This is the first study of the association between inhibitor formation and the causative factor VIII gene mutation in siblings. The data show that the type of mutation provides, to some extent, the basis for this relationship, but the mutation itself is not enough to predict the risk for therapy-induced inhibitor formation.
Department for Coagulation Disorders University Hospital SE-205 02 Malmö, Sweden. Jan.astermark@medforsk.mas.lu.se
Jan
J
Astermark
Johannes
J
Oldenburg
Miguel
M
Escobar
Gilbert C
GC
White
Erik
E
Berntorp
D000328:Adult; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D005169:Factor VIII / Q000235:genetics*; D005192:Family Health; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D012306:Risk; D013548:Sweden
D018389:Codon, Nonsense; D005169:Factor VIII