PMID: 33134807

Gene: VWF

HGNCID:12726

Case: Female patient from the French Caribbean island of Martinique

DiseaseAssertion: VWF Type 3

FamilyInfo: The proband had a combination of two variants p.(Val510+) and p.(Pro21452145Thrfs*5) in a heterozygous state. Her biological profile indicated VWD3: VWF:Ag = 1 to 5%, VWF:RCo = 5%, FVIII:C = 2 to 3%, VWFpp = 6%, and a total absence of multimers assessed by electrophoresis. She was usually treated with plasma-derived VWF concentrates. Interestingly, the VWFpp level in this patient was higher than expected for typical VWD3. The sister who died from a nonhemorrhagic cause had the same clinical-biological profile.

ParentalGenotype(s): The mother had a normal biological assessment and was asymptomatic without any bleeding. Sequencing of the mother's VWF gene revealed a single variant on exon 37: resulting in the nucleotide change c.6432dup / a.a. change p.(Pro2145THRfs*5) which results in a stop codon. This molecular abnormality favors VWD3, even though the mother is asymptomatic. The father experienced excessive bleeding only as a result of trauma or surgery. Sequencing of the father's VWF gene led to the identification of one potential causative variant: p.(Val510 = ), on exon 13 with a nucleotide change c.1530G>A. A second sister of the proband has a clinical and biological phenotype similar to that of her father.

CasePresentingHPOs:HP:0012147, HP:0030132, HP:0030129

CaseHPOFreeText: The proband presented with severe hemorrhagic manifestations.

CaseSubsequentTesting:N/A

GenotypingMethod:NGS

PreviouslyPublished: No

SupplementalData: The prediction softwares used (SpliceSiteFinder-like, MaxEntScan, GeneSplicer, NSPLICE, ESEFinder, RESCUE-ESE, and EX-SKIP) regarding c.1530G > A (p.(Val510 = )) interpreted the appearance of a donor site at 6 base pairs at the end of exon 13 which could potentially alter splicing. This synonymous mutation could therefore have an effect on VWF messenger ribonucleic acid processing, causing a shift in the reading frame and the appearance of a termination codon deletion of two codons. The ACMG predicted that this variant would probably be pathogenic.

VariantEvidence: An additional 21 patients from Martinique were identified with the p.(Val510=) variant. Median age was 63 years (interquartile range [IQR], 45–77) and 65% were female. The striking feature in these patients was a significantly increased VWFpp/VWF:Ag ratio with a median of 5.62 (IQR, 4.36–6,14). This ratio could be calculated only for the 14 patients for whom the VWFpp level was measured. An increased VWFpp/VWF:Ag ratio (> 2.2) is indicative of an accelerated clearance of VWF. Addition testing in four patients involved DDAVP infusion compared to a patient with a VWD1 mutation that does not cause a clearance defect. The results showed accelerated VWF clearance compared to the control. The author propose to classify patient with the p.(Val510=) variant as Type 1C, a rare subtype that removes VWF more quickly than normal in the blood.

Compound Heterozygote:

GeneName:VWF

Variant: NM_00055.2.5:c.6432dup. (Pro2145Thrfs*5)

ClinVarID1330387

gnomAD:N/A

GeneName: VWF

Variant:NM_000552.3:c.1530G>A, p.(Val510=)

CAIDCA6403368

gnomAD: 0.000001240