What we do realize is that one gene can cause different phenotypes, and one phenotype can be caused by different genes. Now, why is it that a certain genetic condition manifests in different ways, quite often sometimes also at different ages, we still don’t know. There may be epigenetic factors, meaning other genes modifying the expression, or there might be environmental factors, meaning something in the environment, which is also modifying the expression of the gene...
What we do realize is that one gene can cause different phenotypes, and one phenotype can be caused by different genes. Now, why is it that a certain genetic condition manifests in different ways, quite often sometimes also at different ages, we still don’t know. There may be epigenetic factors, meaning other genes modifying the expression, or there might be environmental factors, meaning something in the environment, which is also modifying the expression of the gene. So an exact cause is yet to be determined. It’s very likely that there are possibly both epigenetic and environmental causes relating to different expressions of the gene.
Obviously, it causes a lot of challenges, because again, if I may just use an example of PLA2G6, it can present in childhood as infantile neuroaxonal dystrophy, it may present in young adulthood as cerebellar ataxia, and it may present in some people, again, in young adulthood, or even as adults, as dystonia Parkinsonism. So here’s one gene, similar mutations causing different phenotypes, and that’s, therefore, a very challenging thing for clinicians to know about this. And the other thing is that we keep finding unexpected genes when we don’t expect a particular phenotype to be caused by a particular gene. And it turns up, let’s say, on exome sequencing and so on. So all the time the phenotypic expression is widening.
My suggestion to clinicians is that, despite these challenges, it is very important for the clinicians to recognize the core phenotype. What is the core phenotype? The core phenotypes remain true. So for example, if you consider Huntington’s disease, the core phenotype still remains chorea with dementia and an eye movement disorder. Now, there can be some rare cases where young onset presents with Parkinsonism or some people may present with ticks and so on, but that doesn’t take away from the fact that the large majority, that the core phenotype, remains true. So I would suggest to clinicians that it is upon us to recognize the core phenotypes. There can be these variations, there can be different phenotypes, but the core phenotype is what each of us has to recognize.
