Severe type III von Willebrand's disease caused by deletion of exon 42 of the von Willebrand factor gene: family studies that identify carriers of the condition and a compound heterozygous individual

Abstract

Southern blotting was performed with cDNA probes for the human von Willebrand factor (vWF) gene on six patients with severe type III von Willebrand's disease (vWD). A partial deletion in the 3′ end of the vWF gene was demonstrated in one individual whose parents were related and who had an alloantibody inhibitor to vWF. A resulting novel 2.0- kilobase (kb) EcoRI fragment was used for carrier detection within the patient's family, and seven carriers of this recessive trait were identified. Of the six tested, five had normal or only slightly reduced levels of vWF antigen, but with generally higher levels of factor VIII. The sixth carrier had moderately severe vWD and it is proposed that this patient is heterozygous for the defective vWF gene and a second recessive vWF defect. The novel 2.0-kb EcoRI restriction fragment was cloned and sequenced, and compared with that of the corresponding normal 4.2-kb EcoRI fragment that includes exons 41 and 42 of the vWF gene. A deletion of 2,320 base pairs (bp) which included exon 42, was identified and a novel 182-bp insert was found between the breakpoints. This insert was detected by polymerase chain reaction amplification both in the patient's DNA and in his carrier relatives.

Molecular characterization of Iranian patients with type 3 von Willebrand disease

“…Usually the development of an inhibitory anti-VWF antibody in type 3 VWD is associated with large gene deletions [21][22][23][24]. However, cases have been reported of inhibitors in patients with type 3 VWD with nonsense mutations [11,17,25,26].…”

The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles

“…Partial and total VWF deletions have been reported previously including deletions of single exons [8], multiple exons [9][10][11][12][13] and the entire VWF gene [14][15][16][17]; these deletions however only constitute approximately 10% of all reported type 3 VWD mutations (http://www.group.shef. ac.uk/).…”

In silico analysis highlights the copy number variation mechanism responsible for the historically reported VWF exon 42 deletion

“…2a). The extension of the inserted sequence to 194 bp removed the T>A and A>T mismatches previously reported by Peake and colleagues as occurring between the flanking VWF intron 41 sequence and the sequence observed in the index case [5]. In addition, the extension also highlighted regions of microhomology around the breakpoint junction ( Fig.…”

“…In 1990, Peake and colleagues [5] reported an outof-frame homozygous deletion of exon 42 (ex42del) in a type 3 VWD patient, proposed to introduce a premature stop codon into the VWF sequence within exon 43. Interestingly, unlike other VWF deletion breakpoints described, the breakpoint for this copy number variant (CNV) also had a novel 182 bp insertion at the breakpoint junction derived from an unknown location within the human genome [5].…”