Case: Patient II-3, Female, 67 years (as of Dec 2010 follow-up)
DiseaseAssertion: VWD type 2A, phenotype IIC ("VWD2AIIC-Miami") — a historically named variant of type 2A characterized by paradoxically elevated VWF:Ag with reduced function; dominantly inherited in this family (unlike classic/most VWD2AIIC, which is recessive). Bleeding score 21 (very high; nv <4).
FamilyInfo: Mother of III-1, III-3, and III-5 (all three affected); 4-member, 2-generation pedigree, dominant transmission.
ParentalGenotype(s): NA — her own parents not part of this study.
CasePresentingHPOs: HP:0000421 (Epistaxis), HP:0000132 (Menorrhagia), HP:0001934 (Persistent bleeding after trauma — bleeding from minor wounds), HP:0004846 (Prolonged bleeding after surgery — post-surgical bleeding, bleeding at tooth extraction), HP:0030130 (Impaired VWF collagen binding activity; VWF:CB/Ag ratio 0.18, nv ≥0.8), HP:0030129 (Impaired VWF:RCo; VWF:RCo/Ag ratio 0.22, nv ≥0.8), HP:0030132 (Absence of large VWF multimers)
CaseHPOFreeText: VWF:Ag markedly ELEVATED at 2.50× normal (nv 0.5-1.6). Absolute VWF:RCo 0.54 and VWF:CB 0.46 (both near/within the lower end of normal in absolute terms, nv ≥0.5, but severely reduced relative to the elevated antigen). VWF:GPIbα binding 0.74 absolute / 0.30 ratio. FVIII:C 1.08 (normal, nv ≥0.6) with reduced FVIII-binding ratio (F8Br 0.61, at threshold, nv ≥0.6). VWF propeptide:Ag ratio (ppr) 0.71, reduced (nv 0.8-2.2) — indicates decreased clearance of mature VWF relative to propeptide. PFA-100 closure times markedly prolonged (Epinephrine and ADP both >300 sec, nv ≤165/≤118). Hematoma (bruising) and oral cavity bleeding also reported. Post-partum bleeding ultimately requiring hysterectomy. Historical DDAVP test performed in this patient specifically showed findings consistent with delayed VWF clearance. Oral contraceptive/desmopressin use not specified.
CaseNOTHPOs: NA
CaseNOTHPOFreeText: NA
CasePreviousTesting: Extensive prior negative testing — partial sequencing in the original 1993 study plus subsequent complete Sanger sequencing of all VWF coding exons by multiple independent groups over ~20 years found no candidate mutation. The causative variant was only found via MLPA (multiplex ligation-dependent probe amplification), which detects copy-number changes that exon sequencing alone misses. Not genome-wide; VWF-targeted.
GenotypingMethod: MLPA identified signal gain at exons 9-10 in all 4 family members; confirmed by duplication-junction-specific RT-PCR (sense primer in exon 10, antisense in exon 9) and by RT-PCR/sequencing across exons 8-11. Full genomic characterization (PCR primer walking, RepeatMasker, MFold in silico DNA-folding analysis) defined a complex rearrangement: a 5,047 bp duplication (intron 8 through part of intron 10, including exons 9 and 10) plus two deletions (1,348 bp and 2,301 bp) within intron 10, apparently mediated by inverted Alu repeat elements (proposed mechanism: replication slippage for the duplication, a stable Alu3/Alu4 inverted-repeat DNA secondary structure for the deletion).
PreviouslyPublished: PMID 8324222 (Ledford MR, Rabinowitz I, Sadler JE, Kent JW, Civantos F. "New variant of von Willebrand disease type II with markedly increased levels of von Willebrand factor antigen and dominant mode of inheritance: von Willebrand disease type IIC Miami." Blood. 1993;82:169-75) — this is the original report of this same family.
Gene: VWF
Variant: Heterozygous complex in-frame duplication of VWF exons 9-10 (net transcript-level effect), D1 domain (VWF propeptide region). Recombinant expression studies (not patient-specific, applies to the variant generally): "homozygous" mutant VWF secreted only as dimers (no higher-order multimers); co-expression with WT VWF reproduced the patients' plasma multimer pattern exactly; mutant retained in unusually large intracellular granules colocalizing with PDI in the ER; ADAMTS13 proteolysis was not resistant, but an aberrant extra proteolytic band appeared in both patient plasma and recombinant mutant; infusion of recombinant mutant VWF into VWF-/- mice showed significantly prolonged half-life vs. WT (mean residence time 3.15h vs 1.90h, p=0.015), supporting decreased clearance as the mechanism for the paradoxically elevated VWF:Ag.
HGVS: NM_000552.3:c.998_1156dup (p.Glu333_Pro385dup)
ClinVarID: NA
CAID: NA
gnomAD: NA