Investigators from more than 50 institutions across the globe have developed a high-throughput sequencing platform—the ThromboGenomics platform—targeting 63 genes relevant for inherited bleeding, thrombotic, and platelet disorders (BPDs).
The investigators say this platform provides a “comprehensive and cost-effective strategy” to diagnose BPDs and has a high sensitivity to detect and “shortlist” the causal variants when known to be in a BPD gene.
Molecular analysis is often unavailable for patients with BPDs, with the exception of hemophilia and von Willebrand disease, and this causes delays, often inconclusive molecular diagnoses, and compromises treatment.
So to address this unmet diagnostic need, the investigators sequenced 159 and 137 samples from cases with and without previously known causal BPD variants, respectively.
The platform, along with the processing and filtering methods, has a high sensitivity—100% based on the 159 samples with known causal variants.
The investigators report that the sensitivity remains high even when the variants are unknown—greater than 90% based on 61 samples.
The platform’s variant approach also has a high specificity of greater than 99.5% because it reduces the number of candidates requiring consideration.
The ThromboGenomics platform is already being used by the National Health Service in the United Kingdom.
The platform can identify single nucleotide variants, short insertions/deletions, and large copy number variants. They are then subjected to automated filtering and prioritized for diagnosis, resulting in an average of 5.34 candidate variants per individual.
However, the platform cannot identify inversions, and approximately 45% of severe hemophilia A cases are due to inversions. So the investigators recommend that a simple polymerase chain reaction-based test be performed to exclude those cases prior to high-throughput sequencing.
The investigators indicated that during validation of the ThromboGenomics platform, 13 new BPD genes were found.
Use of the platform, they believe, will reduce the diagnostic delay in reaching a conclusive molecular diagnosis for BPD patients.
And further, they believe that “by facilitating provision of a definitive diagnosis, our platform will bring substantial benefits to the estimated 2 million BPD cases worldwide.”
They described the development of the platform in Blood.
