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Type 2N von Willebrand disease is an autosomal recessive bleeding disorder characterized by a markedly decreased affinity of von Willebrand factor (VWF) for factor VIII (FVIII), resulting in low FVIII levels and a clinical phenotype that can mimic mild hemophilia A. Affected individuals often present with mucocutaneous bleeding, joint hemorrhages, and postpartum hemorrhage, while carriers are typically asymptomatic or have mild laboratory abnormalities. Accurate diagnosis relies on measurement of FVIII binding to VWF and molecular confirmation of pathogenic variants in the VWF gene.
Genetic evidence for the association between VWF and Type 2N von Willebrand disease comes from case series and family studies. In a screening of 177 haemophilia A and 199 type 1 VWD patients, 13 individuals across eight unrelated families had bi-allelic VWF mutations and reduced FVIII binding (PMID:8903002). In a phenotypic‐molecular analysis of 69 subjects, six harbored pathogenic variants in exons 18–23 encoding the FVIII binding site (PMID:8822593). Compound heterozygotes and homozygotes for recurrent mutations such as c.2561G>A (p.Arg854Gln) display the full disease spectrum.
The variant spectrum is dominated by missense changes within the N-terminal D′/D3 domains of mature VWF. The most frequent allele, c.2561G>A (p.Arg854Gln), has been reported in homozygous and compound heterozygous states, often in trans with null or other missense variants (PMID:9692396). Other recurrent mutations include c.70G>A (p.Glu24Lys) and c.2372C>T (p.Thr791Met). No deep‐intronic or structural variants have been routinely documented in type 2N cases.
Segregation analysis supports autosomal recessive inheritance: obligate carriers (parents, siblings) exhibit normal FVIII/VWF ratios, whereas homozygotes and compound heterozygotes present reduced FVIII binding, low FVIII levels, and bleeding episodes. In one family, the phenotype of father, daughter, and son segregated with compound genotypes across three generations (PMID:8903002).
Functional studies provide strong concordance with the human phenotype. Recombinant VWF carrying p.Arg854Gln expressed in COS-7 cells shows impaired secretion, loss of high molecular weight multimers, and dramatically reduced FVIII binding (PMID:1918030). Site-directed mutagenesis of D3 domain residues p.Gln1053His and p.Cys1060Arg similarly yields defective multimerization and FVIII interaction (PMID:12588349). Replacement therapy with VWF concentrate restores FVIII levels in affected individuals, confirming pathogenic loss-of-function.
No conflicting reports have challenged the causal relationship; all identified variants in the FVIII binding region exhibit concordant functional defects. Additional large‐scale sequencing studies continue to expand the mutational spectrum beyond the ClinGen scoring cap.
In summary, there is strong clinical validity for VWF in type 2N VWD based on multiple unrelated probands, clear autosomal recessive segregation, and robust functional validation. Molecular testing for key missense variants, combined with FVIII binding assays, provides a definitive diagnosis and informs genetic counseling and targeted therapy.
Key take-home: Type 2N VWD should be considered in patients with low FVIII/VWF ratios and normal VWF multimers; genotyping of recurrent missense mutations such as c.2561G>A (p.Arg854Gln) enables precise diagnosis and guides appropriate VWF concentrate therapy.
Gene–Disease AssociationStrong19 probands in >8 unrelated families, autosomal recessive segregation, concordant functional data Genetic EvidenceStrong13 families with bi-allelic missense variants in the FVIII binding site, recurrent and private alleles; reached genetic cap Functional EvidenceStrongMultiple COS-7 expression assays of key missense mutations demonstrating impaired multimerization and FVIII binding |