Heart disease, kidney disease and diabetes kill many of us and are highly heritable, yet identical twins rarely die of the same cause, even though they share the same genetics. How can that be? One reason is that there are a lot of causes of death, and while cumulatively their probabilities add up to 1, their individual probabilities are low. Even though twins are a lot more likely than others to die of the same thing, they’re still more likely to die of different things.
Children that suffer from early onset, severe epilepsy without a known external cause typically get a genetic test. For less than a third, the test points to a genetic mutation that explains their condition, but for the majority, the test doesn’t point to anything and their epilepsy remains unexplained.
It may be that the genetic test didn’t find the responsible mutation because it’s not detectable using current genome sequencing technology. Long insertion and deletion mutations and repeat expansions are hard to detect using short-read DNA sequencing. In other cases, we may have found the mutation but erroneously think it’s benign. Alternatively, multiple mutations of small effect may act together to cause the disease. Epigenetics is another possible explanation but plays a negligible role.
As a result, there is no discernible environmental or genetic cause for most cases of severe childhood epilepsies. The diagnostic yield of genetic tests for other severe conditions like cardiomyopathies or kidney disease is similarly low.
If it’s not genetics or the environment, then what? The unsatisfying but probably correct answer is chance. From laboratory experiments, we know that for some model organisms we see a lot of diversity even though their genetics and environment are tightly controlled to be identical. Marbled crayfish are a great example. Genetically identical individuals living in identical laboratory environments can vary vastly in how they look like and behave. The only explanation is noise, or chance, or stochasticity, or whatever you’d like to call it. The same is true for humans.
Nehaveigur 