An Alu-mediated deletion at Xp11.23 leading to Wiskott-Aldrich syndrome

Abstract.

Wiskott-Aldrich syndrome (WAS) is an X-linked disease characterized by thrombocytopenia, eczema and immunodeficiency of varying severity. The WASP gene, mutations of which are responsible for the phenotype, maps to Xp11.23. We describe here a patient with a large deletion in the Xp11.23 region. The deletion, which totals 15.8 kb, begins downstream of DXS1696 and encompasses 13 kb upstream of WASP and includes the distal and proximal promoters and exons 1–6. Analysis of the 5′-boundary region identified sequences missing in the Human Genome database and, as a result, the normal DNA sequence was revised to include 743 bp of novel sequence (AF466616). The patient's upstream breakpoint was localized to an AluSg element within a highly repetitive DNA region containing other Alu elements. A 26-bp recombinogenic element is located downstream of the 5′ breakpoint. A 16-bp sequence just upstream of the 5′ breakpoint shares close homology with the sequence that spans the 3′ breakpoint in intron 6. A heptanucleotide of unknown origin, CAGGGGG, links the 5′ and 3′ breakpoints. To our knowledge this is the largest deletion in a WAS patient.