When even well-posed questions are hard to answer

On Friday, in acknowledgement of Rare Disease Day, our daughter Ellen blogged about living with a rare disease.  She wrote eloquently about her wish to understand why she has this disease, including, if it's a single gene disorder, knowing the causal variant.  She wrote about the advantages of this when navigating a medical system that isn't always sensitive to rare diseases, but in which genetics has become the gold standard.  We fully support her wish to understand why she has this disease, and have tried to help as much as we can. We would do the DNA work ourselves if we could.

Even so, she mentioned that her parents, Ken and I, are skeptics about a lot of genetic research.  Yes, that's true, but another word for that is 'realist'.  We are alive at a time in history when more is known about genes and genomes than ever before, and for decades we've been hearing promises of what this new knowledge will mean for medicine, and the promises roll on.  Once we all have our genomes on a disk, we'll be able to predict and treat whatever it is our DNA foretells.

Lazuli Bunting; rare birds in Central Pennsylvania; Wikipedia, Leander Sylvester Keyser

Except, except, Ellen's genome is on a disk.  Or at least her exome, the protein-coding parts of her genome.  Her disease, hypokalemic periodic paralysis, is one of several forms of periodic paralysis, which have been found to be associated with three different ion channel genes.  At one time a researcher in Germany was offering free genotyping to anyone diagnosed with the disease.  Ellen sent  blood samples, but was told that she doesn't have any of the known causal variants in these genes. She was also involved in a large whole exome study of unexplained Mendelian disease, but all they were able to tell her was that she doesn't have any potentially causal de novo mutations, mutations that neither Ken nor I have.  She is the only family member with HKPP, and as such, the initial question in a search for the cause is whether she has a variant that we don't have, that might be responsible.

And, to her frustration, that is all she knows.  It has been suggested that she go the clinical genetics route, having her DNA tested for known causes of HKPP, but that seems unlikely to be helpful, given that she knows what disease she has, just doesn't know why, and clinical labs don't look for new causal genes or variants, but instead a battery of those that are known.

Ellen has classic symptoms and classic triggers, and her disease is pretty well controlled at the moment, so identifying the cause, as she wrote in her post, might not change her treatment, but it would ease her mind about future dealings with the medical system.  As importantly, it might help future patients avoid the lengthy, destructive diagnostic odyssey she herself experienced, which itself would be a very satisfying outcome.

Big Data advocates will say that the problem is that not enough people with HKPP have been sequenced, and once we've got a million genomes or more, that will facilitate identifying Ellen's and others' causal variants.  But only 1 in 200,000 people have HKPP, so one million is unlikely to help.  And, though the data are rather sparse, some estimates based on those data suggest that a fairly large minority, a third or so, won't have one of the known causal genetic variants.  As with most diseases, the phenotypes vary greatly, and again as with most diseases, this is likely to be because every genome is unique, and genetic background matters, along with exposure to other triggering factors.

Perhaps there's an as-yet unidentified gene that would explain many of the unidentified cases, or there are many unique pathways to the disease, or both, but given the rarity and the heterogeneity of the periodic paralyses, it would take a huge amount of luck for even a large database to answer Ellen's question.  We should perhaps call it dumb luck, because the investigators vacuum up generic data without specific regard to, say, the physiology of this particular disorder (and the same for countless other disorders).  Of course, collecting data on every possible physiological or environmental factor, mostly with weak individual effects, isn't possible and that is a dilemma for modern public health science.

In addition, it's known from affected families that penetrance of alleles related to the periodic paralyses is not 100% -- some people with a 'causal' variant never experience an attack, making associating genotype with phenotype even harder.  Again, genetic background may affect this but, as with many genetic disorders with variable penetrance, it's not at all clear.  Incomplete penetrance is a fact, but also a fudge factor, because it leaves the impression the trait really is 'genetic'; in fact, we often don't know how many people have such mutations but no symptoms at all, because they aren't screened (but some studies looking for such asymptomatic cases have easily found them, and they can be as common as the 'causal' mutations in affected patients).

Further, it's possible that there are non-ion channel related causes of these channelopathies.  That is, something upstream is going wrong.  In that case, it's unclear where to even begin to look for genetic causation.  Thus, hypothetically in this instance, ion channels respond to the ionic concentrations inside the cell and in its environs.  Factors that affect the ion concentrations themselves could lead to effects similar to ion channel defects per se.  Thus, again just surmising, there are known environmental stimuli for attacks but these may affect the ion concentrations themselves, not the channel protein function.  And, of course, both could be at work, which would be rather expected given the many precedents for disease complexity.

And, it's possible that Ellen's disease is polygenic, or not genetic at all, though given that many cases of periodic paralysis, including in families, seem to have a single genetic cause, this seems unlikely.

Genetics asks two basic questions: What causes disease X?  And, who will get it?  The promises of the past few decades are that answers to both these questions are just around the corner for most diseases.  The NIH Office of Rare Disease Research reports that there are 7000 known rare diseases (diseases that affect fewer than 1 in 200,000 people).  The cause of many of these diseases has been identified, and by some criteria over 6000 specific genes have been associated with some usually rare single-gene disorder.  In many cases, it's possible to predict who will get the disease, and that is where genetic counseling is so useful.  It is, in our view, also where our limited research resources should be directed.  

But, if you read MT at all regularly, you know what we think about the promise of predicting common, complex diseases with genes.  Current science is very far from answering the two simple questions, what causes common, complex disease X?, and who will get it?  And, you know that we think that's because these questions can't be answered in any way approximating the promise of, say, precision medicine.  

But single-gene disorders are a different kind of problem.  What causes Ellen's HKPP? That seems to be a well-posed question, and should be answerable.  But to date, it hasn't been.  Labs are reporting 25-30% success with identifying the cause of rare genetic diseases (some somewhat higher success rates), so she is not at all unique.   We commented last week on the problem of identifying specific at-risk subgroups more effectively than blanket epidemiological studies currently can.

Are we skeptics?  Or are we realists?  When even the 'easy' cases, like Ellen's, the low-hanging fruit, are hard, what does this mean about the promises for genomics?