1. ¹Thrombosis and Haemostasis Unit, Department of Haematology and Oncology, Giannina Gaslini Institute, Genova, Italy
2. ²McKusick Nathans Institute of Genetic Medicine, The Johns Hopkins University, Baltimore, MD, USA
3. ³Laboratory of Pre- and Post-natal Diagnosis of Metabolic Diseases, Giannina Gaslini Institute, Genova, Italy
4. ⁴Cancer Cytogenetics Unit, Giannina Gaslini Institute, Genova, Italy

Correspondence: Dr M Pasino, Thrombosis and Haemostasis Unit, Department of Haematology and Oncology, G Gaslini Institute, Largo G Gaslini no. 5, Genova 16147, Italy. Tel: +39 010 5636277; Fax: +39 010 386204; E-mail: mirellapasino@ospedale-gaslini.ge.it

Received 22 July 2004; Revised 12 January 2005; Accepted 19 January 2005; Published online 2 March 2005.

Abstract

A basic tenet of the Lyon hypothesis is that X inactivation occurs randomly with respect to parental origin of the X chromosome. Yet, nonrandom patterns of X inactivation are common – often ascertained in women who manifest recessive X-linked disorders despite being heterozygous for the mutation. Usually, the cause of skewing is cell selection disfavouring one of the cell lineages created by random X inactivation. We have identified a three generation kindred, with three females who have haemophilia A because of extreme skewing of X inactivation. Although they have both normal and mutant factor VIII (FVIII) alleles, only the mutant one is transcribed; and, they share an XIST allele that is never transcribed. The skewing in this case seems to result from an abnormality in the initial choice process, which prevents the chromosome bearing the mutant FVIII allele from being an inactive X.