Unbalanced X-chromosome inactivation with a novel FVIII gene mutation resulting in severe hemophilia A in a female

This report is of a 14-month-old girl affected with severe hemophilia A. Bo th her parents had normal values for factor VIII activity, and von Willebra nd disease type 2N was excluded. Karyotype analysis demonstrated no obvious alteration, and BcA Southern blot did not reveal F8 gene inversions. Direc t sequencing of F8 gene exons revealed a frameshift-stop mutation (Q565delC /ter566) in the heterozygous state in the proposita only. F8 gene polymorph ism analysis indicated that the mutation must have occurred de novo in the paternal germline. Furthermore, analysis of the pattern of X chromosome met hylation at the human androgen receptor gene locus demonstrated a skewed in activation of the derived maternal X chromosome from the lymphocytes of the proband's DNA. Thus, the severe hemophilia A in the proposita results from a de novo F8 gene frameshift-stop mutation on the paternally derived X chr omosome, associated with a nonrandom pattern of inactivation of the materna lly derived X chromosome. (Blood. 2000;96: 4373-4375) (C) 2000 by The Ameri can Society of Hematology.