Background and objectives: von Willebrand disease (VWD) type 3 is characterized by extremely low levels of von Willebrand factor (VWF) in plasma. To date, only 11 examples of gross deletions have been reported for the VWF gene and the underlying mutational mechanisms remain unclear. A Chinese patient with type 3 VWD was studied to elucidate the underlying mechanism of mutagenesis.
Design and methods: PCR was designed to amplify across the putatively deleted region of genomic DNA from the patient and his parents to locate the deletion breakpoints. In silico analysis was then performed to search for repetitive sequence elements, recombination-associated motifs, and scaffold/matrix attachment regions (S/MARs).
Results: A novel homozygous gross deletion of the VWF gene, which removes some 61044 bp DNA between introns 5 and 16, was identified in the patient. The deletion junctions were flanked by highly homologous Alu repeats in inverted orientation. These repeats could thus have potentiated the formation of a stem-loop structure thereby bringing the breakpoints into close proximity. A number of recombination-associated motifs were noted in close proximity to both deletion breakpoints. Both the 5' and 3' breakpoints were located in, or near, regions with a high propensity to form S/MARs.
Interpretation and conclusions: We report the first example of an Alu-mediated VWF gross gene deletion. Since a number of recombination-associated motifs were also identified in the vicinity of the breakpoints, it may be that multiple sequence elements have acted in concert to give rise to this deletion event.