Even single-gene disorders are complex

We've written a lot about complex disease in this blog, but we thought it was now time to give the complexity of single-gene disorders its due. Genes for what are often called 'simple' Mendelian traits (traits that are inherited in families in predictable patterns) are much easier to find than genes for complex traits like heart disease or asthma, but that doesn't make them simple.

In part, it's easier to define a 'simple' trait--for example, some forms of oligodontia, or missing teeth, run in families and most forms are due to mutations in Msx1 or Pax9. But it turns out that even a trait that should be easy to define isn't so straightforward--when multiple family members are affected they aren't always missing the same teeth, or the same number of teeth. So, there's something about the timing of the initiation of teeth during development that varies, and probably not by much, but enough to make the phenotype unpredictable, and the variation may well be random.

And, of course more complex phenotypes are even more unpredictable, even if due to single genes. A rare genetic disorder called hypokalemic periodic paralysis (hkpp) is one such trait. This is a channelopathy, an ion channel disorder, usually of sodium ion channels, which regulate the flow of ions into and out of the cell, but in individuals with hkpp, they let potassium into muscle cells but don't let it out in a timely way, thus weakening or paralyzing the muscle.

Hkpp involves anything from fleeting weakness to full paralysis, and in rare cases can be fatal if breathing is involved. The attacks generally resolve within hours, or sooner if the individual consumes potassium, but sometimes can linger for weeks. There are known 'triggers', including heat, hunger, sugar, carbohydrates, alcohol, exercise, and rest after exercise, but attacks can happen even without a trigger, and not everyone shares all the same triggers. So, in a sense this would seem to be a classic case of gene by environment interaction--sometimes. Why is there no apparent trigger for some attacks? And, it's interesting that age of onset is typically during adolescence--so why were these channels seemingly doing their job properly during the active childhood years?

Causative mutations have been found in at least three genes, and have been traced in families, but 30% of the families with this disorder don't have mutations in these genes (and often don't share the classic food triggers), and individuals with the same mutation within an affected family can have very different forms of the disorder, from no symptoms at all to just one in their lives to daily episodes of full paralysis.

A similar description could be written for most 'simple' single-gene disorders. The more common the trait, or the more intensely it has been studied, the more this has been shown. Usually, the story is different in different populations, and this is what would be expected on grounds of evolution (population history): in each region of the world, different mutations have arisen or risen in frequency, there are different environmental exposures, and the genomic background (variation at genes other than the 'causal' gene) differs, even with similar phenotypes.

The classic examples are diseases like PKU, cystic fibrosis, and even genes related to resistance to malaria (like sickle-cell hemoglobin). Even the once-simple ABO blood group system is like this. So, if simple diseases are so complex, it's no wonder that complex diseases are so hard to understand.