There are two related VUS problems: (1) don’t know if the variant has a functional clinical impact and (2) not sure whether the magnitude of the impact is severe enough to cause a specific pathologic effect.
The industry needs to separate those separate inquiries, and introduce a clearer way to catalog the direct functional impact of gene variants irrespective of big-impact pathologies. For example, knowing a gene variant reduces dopamine recycling 15% is interesting and useful and completely separate from whether low dopamine recycling is clinically harmless, pathological or unknown. Such a gene is not an unknown quantity, and the current reporting protocols conflate and confuse these important topics.
Great overview of one key problem in prediction from genotypes.
So many more to go: oligogenic and polygenic models and then epistasis and gene-by-environmental interactions, epigenetic controls, translation controls …
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[ 2.7 ms ] story [ 13.1 ms ] threadThe industry needs to separate those separate inquiries, and introduce a clearer way to catalog the direct functional impact of gene variants irrespective of big-impact pathologies. For example, knowing a gene variant reduces dopamine recycling 15% is interesting and useful and completely separate from whether low dopamine recycling is clinically harmless, pathological or unknown. Such a gene is not an unknown quantity, and the current reporting protocols conflate and confuse these important topics.
So many more to go: oligogenic and polygenic models and then epistasis and gene-by-environmental interactions, epigenetic controls, translation controls …