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.
FollowingTheDao•5mo ago
I agree with you 100%! I think the whole focus on pathological versus non-pathological is two black-and-white. There can be many genetic changes that can slow down the function of an enzyme,enough that can affect a person without clearcut pathology, but yet the patient suffers.
To me these changes are more important than the pathological ones. But they’re just not as sexy and the risks of suffering pathology from these is dependent, not only on the jeans, but also on the environment.
For example, you can look at the polymorphisms and the fatty acid desaturate genes and know that your diet can impact your long-term health because of the way you process poly unsaturated fatty acids.
As for your dopamine example, what does this mean if someone is deficient in B6 or iron which help make dopamine? Isn’t that more important for this person? And what if this person drinks too much? Does that make them more prone to addiction? These are the things that affect every day people and make their lives better and understanding the risks that are associated with their genetics.
By the way, I’m a success story about modern genetics. I’ve discovered that my family carries mutation in the CBS gene (D270N), that does not allow P5P to attach to the enzyme correctly, leading us to have a functional B6 deficiency and the host of issues.
robwwilliams•5mo ago
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 …
unyttigfjelltol•5mo ago
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.
FollowingTheDao•5mo ago
To me these changes are more important than the pathological ones. But they’re just not as sexy and the risks of suffering pathology from these is dependent, not only on the jeans, but also on the environment.
For example, you can look at the polymorphisms and the fatty acid desaturate genes and know that your diet can impact your long-term health because of the way you process poly unsaturated fatty acids.
As for your dopamine example, what does this mean if someone is deficient in B6 or iron which help make dopamine? Isn’t that more important for this person? And what if this person drinks too much? Does that make them more prone to addiction? These are the things that affect every day people and make their lives better and understanding the risks that are associated with their genetics.
By the way, I’m a success story about modern genetics. I’ve discovered that my family carries mutation in the CBS gene (D270N), that does not allow P5P to attach to the enzyme correctly, leading us to have a functional B6 deficiency and the host of issues.