VWF – von Willebrand disease type 3

Type 3 von Willebrand disease (VWD3) is the most severe form of VWD, characterized by virtually undetectable plasma and platelet von Willebrand factor (VWF) leading to severe mucocutaneous and deep‐tissue bleeding. The disorder follows an autosomal recessive inheritance pattern due to biallelic loss‐of‐function mutations in VWF. Genetic testing is critical for diagnosis and family counseling in affected pedigrees.

Autosomal recessive inheritance of VWD3 has been established in multiple cohorts: 32 probands from 28 German families showed extensive haplotype diversity and identified defects on 14/56 chromosomes (PMID:7989040). In Swedish and Finnish patients, 11 probands were homozygous and 8 compound heterozygous for VWF mutations among 24 families (PMID:8088787). Iranian and Indian–Greek cohorts confirmed wholly homozygous null alleles in consanguineous pedigrees (PMID:19500169; PMID:18485763). Recurrent homozygous nonsense variants (e.g., c.4696C>T (p.Arg1566Ter)) were reported in consanguineous Chinese families (PMID:31793247).

The variant spectrum in VWD3 exceeds 70 distinct alleles, encompassing gross deletions, frameshifts, nonsense, splice‐site, and missense changes. A hotspot single‐base deletion c.2435del (p.Pro812fs) recurs in German and Baltic cohorts (PMID:7989040; PMID:23834637). Additional common alleles include c.4975C>T (p.Arg1659Ter) in Finland and c.460_480del (p.Tyr154_Gly160del) in Nordic populations (PMID:8088787).

Functional assays demonstrate that many null alleles produce stable mRNA but misfolded or retained protein. Propeptide missense mutations p.Asp141Tyr and p.Cys275Ser reduce secretion to ~15% of wild type and impair multimerization in COS‐7 cells, confirming recessive pathogenicity (PMID:18328061). The common c.2435del frameshift yields truncated protein with defective propeptide processing and intracellular retention (PMID:8857958).

Mechanistically, VWD3 arises from biallelic loss‐of‐function alleles leading to near‐complete VWF deficiency without dominant‐negative interference. The concordance of genetic, segregation, and functional data across diverse populations provides strong evidence for a definitive gene–disease association.

Key Take-home: Comprehensive VWF genotyping, including hotspot and novel variants, is essential for accurate diagnosis, management, and genetic counseling in autosomal recessive type 3 von Willebrand disease.

References

• Human genetics • 1994 • Genetic heterogeneity of severe von Willebrand disease type III in the German population. PMID:7989040
• Genomics • 1994 • Characterization of the von Willebrand factor gene (VWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin. PMID:8088787
• Haemophilia • 2008 • Expression studies of missense mutations p.D141Y, p.C275S located in the propeptide of von Willebrand factor in patients with type 3 von Willebrand disease. PMID:18328061
• British journal of haematology • 1996 • A common frameshift mutation in von Willebrand factor does not alter mRNA stability but interferes with normal propeptide processing. PMID:8857958
• Haemophilia • 2013 • Phenotypic and genotypic characterization of 10 Finnish patients with von Willebrand disease type 3: discovery of two main mutations. PMID:23834637
• Molecular genetics & genomic medicine • 2020 • Two cases of von Willebrand disease type 3 in consanguineous Chinese families. PMID:31793247

Evidence Based Scoring (AI generated)