A patient with von Willebrand's disease characterized by a compound heterozygosity for a substitution of Arg by Gln in the putative factor‐VIII‐binding domain of von Willebrand factor (vWF) on one allele and very low levels of mRNA from the second vWF allele

Abstract

We describe a patient with a lifelong bleeding disorder previously classified as von Willebrand's disease (vWD) type I. The factor VIII (FVIII) level in this patient was disproportionately low and we showed that this was due to a decreased factor VIII binding capacity of her vWF. To characterize the molecular defect in this type of vWD, a cDNA-dependent polymerase chain reaction (PCR) amplification was performed using platelet RNA as a template. Direct sequencing of the amplified fragment, which encodes for the FVIII-binding domain, showed a single nucleotide change in exon 20 at codon 854, resulting in the substitution of CAG glutamine (Gln) for CGG arginine (Arg). At the level of the cDNA only the mutated sequence was found, whereas at genomic DNA level the patient was heterozygous for this mutation. This patient is therefore a compound heterozygote for a point mutation resulting in a FVIII-binding defect and a vWF allele with low transcript levels.

Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

“…rs7962217 was associated with higher FVIII levels whereas rs41276738 was associated with lower levels and had an effect size similar to that of the strongest genetic predictor of FVIII levels, the O-deletion tagging SNP (rs657152). rs41276738 has been reported in patients with von Willebrand disease type 1 34,35 and type 2N, [36][37][38][39][40][41][42][43] but the association with vWF levels did not reach exome-wide significance, although its direction was consistent with the direction of effects on FVIII. The STAB2 variant rs141041254 was associated with higher plasma levels of both FVIII and vWF.…”

“…Some of the variants have been found in patients with diseases related to blood clotting, which suggests that these genes and their uncommon and rare genetic variation may play a role in a clinical phenotype. [26][27][28][32][33][34][35][36][37][38][39][40][41][42][43] The distribution of the phenotypes within our research populations were within the extremes of a clinically activity, and 2% to 297% antigen; FVIII: 14% to 500% activity; and vWF: 2% to 374% antigen). Furthermore, the magnitude of difference in the phenotype associated with the variant was mostly modest, although some were larger and were associated with a change equivalent to half the size of the estimated population mean for the phenotype of interest.…”

Lack of F8 mRNA: a novel mechanism leading to hemophilia A

“…17 In addition to these genes, pathologic monoallelic expression in disease-related genes were also reported. [18][19][20] For example, congenital hypothyroidism is a recessive disease caused by mutations in thyroid peroxidase (TPO); patients are usually homozygous or compound heterozygous for gene mutations. In some 17% of the cases there is only one mutated allele; in one of these cases Fugazzola et al 18 showed that the intact allele on the DNA level is unexpressed and undetectable on the RNA level.…”

Factor VIII-von Willebrand Factor Binding Defects in Autosomal Recessive von Willebrand Disease Type Normandy and in Mild Hemophilia A

“…2 Response to DDAVP in patients with mild/moderate hemophilia A ( a ; Peerlinck et al [18]) and type 2 VWD ( b ; Mazurier et al [19]). b VWD Normandy Arg53Trp = R816W VWF gene mutation. …”

“…Patients are either homozygous for type 2N mutations or compound heterozygous carrying two type 2N mutations. Compound heterozygosity for a VWD 2N mutation and a quantitative defect on the second allele are also frequent [17, 18]. …”