X-linked thrombocytopenia in a female with a complex familial pattern of X-chromosome inactivation

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, eczema and various degrees of immune deficiency caused by mutations in the WAS gene, which encodes the WASP protein, the expression of which is restricted to haematopoietic cells. Mild allelic variants are associated with X-linked thrombocytopenia (XLT). Female carriers tend in general to be asymptomatic as a consequence of a positive selection of cells with an active normal X chromosome, which results in a non-random inactivation of the mutated gene in affected cell lineages. We report on six female members of the same family carrying the mutated WAS allele p.V332A, which is known to be associated with XLT. One of them had presented severe thrombocytopenia from birth. Western blotting showed the WASP protein in peripheral blood cells to be normal in size and expression, and scanning electron microscopy revealed a normal distribution of microvilli on T cells. X-chromosome inactivation-pattern analysis showed total inactivation of the non-mutated paternal X chromosome in the patient's peripheral blood cells. All the other female family members were healthy and presented varying X-chromosome inactivation patterns, ranging from random X chromosome inactivation to total X-chromosome inactivation of the mutated chromosome. Our results in these female carriers of p.V332A show that manifestation of the disease requires a total inactivation of the non-mutated X chromosome and allow us to confirm that clinical manifestations in female carriers are highly dependent not only on the mutation characteristics but also on the X-chromosome inactivation pattern of affected line.