Photo courtesy of NIGMS
A study of genes associated with bleeding disorders suggests it can be challenging to gauge the clinical significance of novel gene variants.
Researchers analyzed genomic data from more than 16,000 subjects, looking for missense variants in the integrin aIIbß3 receptor subunit genes ITGA2B and ITGB3.
Although the team identified close to 200 novel variants in these genes, they found it difficult to determine the functional impact of the variants.
Barry S. Coller, MD, of The Rockefeller University in New York, New York, and his colleagues described this research in PNAS.
The team analyzed genomic data from 16,108 people and found that about 1.3% of the individuals had missense variants in ITGA2B, ITGB3, or both genes.
To determine which of these missense variants were newly discovered, the researchers looked for 111 variants that were previously reported as being associated with Glanzmann thrombasthenia, 20 variants that were associated with alloimmune thrombocytopenia, and 5 variants that were associated with aniso/macrothrombocytopenia.
The results suggested the team had discovered 114 novel missense variants in ITGA2B and 68 novel variants in ITGB3. And they did not find any of the previously reported variants in the 2 genes.
“This means the disease-causing mutations previously reported are very rare and, thus, probably first appeared relatively recently—that is, in the past several hundred years,” Dr Coller said.
The researchers then used 3 different algorithms to try to predict the proportion of the missense variants that would likely have a negative impact on a person’s health by causing excess bleeding.
They got a wide range of results. Depending on the algorithm and other variables, between 27% and 71% of variants were predicted to be harmful.
To test the validity of the predictions, the team took a closer look at 3 of the variants that affect amino acids previously associated with Glanzmann thrombasthenia.
They found that 2 of the variants—aIIb P176H and ß3 C547G—severely reduced aIIbß3 expression. The third variant—aIIb P943A—partially reduced aIIbß3 expression but had no effect on fibrinogen binding.
These results show how challenging it can be to interpret genetic data, Dr Coller said.
“Some variants of these 2 genes will likely be obviously deleterious, but it may be impossible to predict whether others are deleterious,” he noted. “In those cases, we will need to use additional information to judge the likelihood of a mutation being deleterious, and, in many cases, there will be residual uncertainty.”
