David Green, MD, PhD reviewing Simeoni I et al. Blood 2016 Jun 9.
The ThromboGenomics platform provides a sensitive test to diagnose inherited bleeding, thrombotic, and platelet disorders.
Genetic studies have enhanced diagnostic accuracy for many bleeding and clotting disorders, such as hemophilia, von Willebrand disease, platelet defects, and venous thromboembolism. But even though the whole genome or prespecified regions of the genome have been sequenced, the clinical relevance of mutations discovered during sequencing is often uncertain. To address this concern, international investigators constructed a high-throughput sequencing platform (ThromboGenomics) and assessed its accuracy in detecting causal variants in 63 genes associated with bleeding disorders. A multidisciplinary team reviewed patient phenotypes and sequencing results and declared whether variants were pathogenic.
Sequencing of 159 samples from 61 patients with established hemorrhagic disorders recapitulated all previously detected causal variants and led to a molecular diagnosis in 56. The platform identified 44 single nucleotide variants, 13 insertion-deletions, and 1 duplication; 28 of the variants were novel. Sequencing of 137 samples from 76 patients without previously known causal variants resulted in a molecular diagnosis in only 8, suggesting that potentially informative genes had not been sequenced. Overall, the platform identified 204 distinct pathogenic variants, with excellent reproducibility. A limitation is that the platform is unable to identify inversions, which occur in ~45% of patients with severe hemophilia; an alternative method, such as the polymerase chain reaction test, should be used to detect inversions and exclude them prior to high-throughput sequencing.
Simeoni I et al. A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders. Blood 2016 Jun 9; 127:2791.