New study shows genetic testing may refine von Willebrand diagnosis
Findings highlight value of combining lab parameters with genetic analysis
Written by |
Taking both laboratory parameters and genetic testing into account can improve diagnostic accuracy in people with von Willebrand disease (VWD), according to a study in Belgium.
The study identified 126 unique variants in the VWF gene, including 58 that had not been reported before, among participants who underwent genetic testing. Although genetic testing confirmed laboratory findings in most cases, in about one-third, the diagnosis was refined or clarified after genetic analysis.
Combining lab tests and genetics may improve diagnosis
This study “demonstrates that a comprehensive evaluation combining laboratory [parameters] … and extensive genetic screening provides critical insights into the diagnosis and classification of VWD,” the researchers wrote.
The study, “Mapping Laboratory Phenotype–Genotype in Von Willebrand Disease: A Belgian National Survey,” was published in Thrombosis and Haemostasis.
VWD is a bleeding disorder caused by low levels or reduced activity of von Willebrand factor (VWF), a protein that helps with blood clotting, most often linked to changes (mutations) in the VWF gene. As a result, the body cannot properly form blood clots, leading to abnormally heavy or prolonged bleeding.
Because symptoms of VWD can vary widely, the condition can be difficult to diagnose and classify.
Here, researchers analyzed data from the B-Will Study, a national survey of patients with suspected or known VWD in university hospitals and large regional hospitals in Belgium. The study aimed to better understand how genetic differences are linked to disease features in VWD.
A total of 587 patients took part, representing 434 families with suspected or known VWD. DNA was available for 361 participants. Overall, 511 patients were confirmed to have VWD, including 391 probands (the first identified patient in a family) and 120 family members.
Patients were first classified using laboratory testing
Participants were first classified based on laboratory parameters, including VWF levels, activity of clotting factor VIII, and VWF’s ability to bind platelets (cell fragments needed for blood clotting).
VWD type 1 was the predominant type, diagnosed in about 53% of patients, followed by type 2 (44.8%). In type 1, VWF levels are lower than normal, while in type 2, patients produce a form of VWF that doesn’t function correctly.
A test called VWF multimer analysis, which looks at different sizes of the VWF protein, was available for 323 patients. These patterns help determine VWD subtypes. In most cases (75%), the VWF multimer pattern was consistent with laboratory parameters, but 25% showed differences.
For instance, among patients initially classified as type 1 based on laboratory parameters, 18% showed loss of larger VWF multimers, which is typical of some type 2 forms.
Among 289 participants who underwent genetic testing, 92.7% had at least one disease-linked variant. Most had only one variant in the VWF gene.
“While the variant detection rate was high, some patients lacked identifiable genetic variants, underscoring the limitations of current genetic testing methods and the need for continued advancements in genetic analysis technologies,” the researchers wrote.
Genetic testing identified known and novel VWF variants
A total of 126 unique variants were identified, including 58 novel variants in 91 patients, more commonly in those with VWD type 1. Most were missense variants — point mutations in DNA that lead to a different amino acid in the resulting VWF protein.
“In regions where population migration and admixture have been historically significant, the admixture of ethnic groups may account for both the emergence of novel variants and the altered prevalence of specific VWD subtypes,” the investigators wrote.
Genetic variants and multimer patterns confirmed the proposed diagnosis based on laboratory parameters in two-thirds of the 247 participants with available data for all analyses.
Among the 247 patients with complete data from all analyses, nearly one-third (84) had their diagnosis reclassified after genetic and multimer findings were considered. This group included 47 participants whose laboratory parameters suggested VWD type 1 but who were reclassified as type 2, 15 who were identified as having a different type 2 subtype, and eight initially diagnosed with type 2 who were ultimately identified as type 1.
“Our study, consistent with other population-based investigations, suggests that the evolution in diagnostic strategies for VWD must adapt to the genetic diversity shaped by historical and contemporary migration patterns,” the researchers wrote.
