Submitted January 31, 2002
Accepted April 15, 2002
Skewed X-chromosome inactivation in monochorionic diamniotic twin sisters results in severe and mild hemophilia A
Sophie Valleix, Christine Vinciguerra, Jean-Maurice Lavergne, Marco Leuer, Marc Delpech, and Claude Negrier*
Laboratoire de Biochimie et Genetique Moleculaire, Faculte Cochin-Port Royal, Paris, France
Centre de Traitement de l'Hemophilie, Laboratoire d'Hemostase, Inserm U331, Hopital Edouard Herriot, Lyon, France
Laboratoire d'Hemostase et Thrombose, Inserm U143, Hopital de Bicetre, Le Kremlin Bicetre, France
Department of Clinical Biochemistry, University of Bonn, Bonn, Germany; Biopsytec Analytik GmbH, Rheinbach, Germany
* Corresponding author; email: negrier{at}laennec.univ-lyon1.fr.
This study describes the genetic mechanisms responsible for the de novo occurrence of severe and mild hemophilia A in monozygotic twin females. Both twins were found to carry a previously known factor VIII mutation (Y16C) in the heterozygous state which most probably arose in the paternal germ-line. Both twins showed concordant skewing of X-inactivation towards the maternally-derived normal X-chromosome, the most severely affected twin exhibiting a higher percentage of inactivation of the normal X-chromosome. The degree of skewing of X-inactivation closely correlated with both the coagulation parameters and the clinical phenotype of the twins. Since these twins were monochorionic, such results suggest that the twinning event in this case has occurred after the onset of the X-inactivation period.
