Case: Proband, female, 27 years old at report; ethnicity not reported.
DiseaseAssertion: VWD2A. The authors confirmed type 2A VWD based on VWF:Ac/VWF:Ag ratio <0.7 (excluding types 1C, 2N, and 3), RIPA negative for increased platelet affinity (excluding type 2B), and multimer analysis showing HMWM deletion with IMWM reduction (excluding type 2M).
FamilyInfo: The patient denied a family history of abnormal bleeding. The father carried VWF c.2281+1G>A and was not diagnosed with VWD (VWF:Ag 61%, VWF:Ac 60.6%, FVIII activity 82%, VWF:Ac/VWF:Ag ratio 0.9). The mother carried VWF c.4654T>A and was diagnosed by the authors as having low VWF per British Committee for Standards in Haematology criteria (VWF:Ag 40%, VWF:Ac 26.6%, FVIII activity 66%, VWF:Ac/VWF:Ag ratio 0.6). Neither parent had a history of abnormal bleeding. Parental laboratory results and genotypes are reported in Table 2.
ParentalGenotype: Both parents were genotyped. The father was heterozygous for c.2281+1G>A and the mother was heterozygous for c.4654T>A (Table 2). The authors report that the two variants were inherited separately from each parent, establishing compound heterozygosity. Note: Figure 2 shows Sanger sequencing validation for c.2281+1G>A only, confirming the variant in the patient and father and a normal genotype at that locus in the mother. No confirmatory sequencing trace is shown for the maternal c.4654T>A variant; that genotype is reported only in Table 2.
CasePresentingHPOs: HP:0000421, HP:0000132, HP:0004846, HP:0012147, HP:0030132, HP:0011871
(Epistaxis, Menorrhagia, Prolonged bleeding after surgery, Reduced quantity of VWF, Absence of large von Willebrand factor multimers, Impaired RIPA)
CaseHPOFreeText: Gingival bleeding persisted for two days after tooth extraction. History of frequent epistaxis and one episode of heavy menorrhagia in 2007 treated with plasma transfusion. ISTH-BAT bleeding score 7 (epistaxis score 1, bleeding after tooth extraction score 2, heavy menorrhagia with plasma transfusion score 4). VWF:Ag 26.2%, VWF:Ac 5.7%, FVIII activity 43%, VWF:Ac/VWF:Ag ratio 0.21. Low-concentration RIPA 23.7% (reference 30.0-70.0%). VWF multimer analysis demonstrated deletion of high-molecular-weight multimers and reduction of intermediate-molecular-weight multimers (Figure 1). Arachidonic acid-induced platelet aggregation was impaired, with a maximal aggregation rate of 14.3%.
CaseNotHPOs: HP:0003645, HP:0001873
(Prolonged partial thromboplastin time, Thrombocytopenia)
CaseNotHPOFreeText: APTT 39.2 s (reference 32.0-45.0), platelets 183x10^9/L (reference 125-350), PT 13.6 s (reference 11.0-15.0), and fibrinogen 2.71 g/L (reference 2.0-4.0) were all within reference ranges, as was thrombin time. High-concentration RIPA 52.9% (reference 40.0-80.0), normal. Systemic physical examination unremarkable with no active bleeding on admission. Prior laparoscopic surgery for luteal rupture without a remarkable increase in bleeding. Hemoglobin 125 g/L was marginally below the stated reference range (130-175), although the authors described the complete blood count as normal.
CasePreviousTesting: Whole-exome sequencing was performed, which is a genome-wide method. No genes other than VWF were reported as tested or implicated. No earlier molecular genetic testing was reported.
GenotypingMethod: Whole-exome sequencing followed by one-generation (Sanger) sequencing validation, performed on the proband and both parents.
Variant 1
Gene: VWF
Variant: c.2281+1G>A, heterozygous, inherited from the father. Intron 17 canonical splice donor site; the authors describe the affected region as lying between the D2 and D' domains. Classified as pathogenic by the authors per ACMG guidelines.
HGVS: NM_000552.5:c.2281+1G>A
ClinVar: NA
CAID: CA383523243
gnomAD: Absent (gnomAD v4.1.1; variant not found, region adequately covered)
Variant 2
Gene: VWF
Variant: c.4654T>A (p.Phe1552Ile), heterozygous, inherited from the mother. Exon 28, A2 domain; missense. Classified as a variant of uncertain significance by the authors per ACMG guidelines. Note: the article gives the protein consequence as p.Phe1152Ile in the Case Presentation and p.Phe1552Ile in the Discussion; these are internally inconsistent. p.Phe1552Ile is correct, as confirmed by HGVS validation and by the ClinGen Allele Registry record (NP_000543.3:p.Phe1552Ile), and is consistent with the stated exon 28 location.
HGVS: NM_000552.5:c.4654T>A (p.Phe1552Ile)
ClinVar: NA
CAID: CA383500446
gnomAD: Absent (gnomAD v4.1.1; variant not found, region adequately covered)