Tuesday, November 10, 2009

Occult Genetic Disease

A clinical aside by Dr. Steve over at Gene Sherpas piqued my interested recently. He mentioned a 74 year old female patient of his with lung difficulties who turned out positive both by the sweat test and genetic testing for cystic fibrosis. One of her grandchildren had CF, which appears to have been a key hint in this direction. This anecdote was particularly striking to me because I had recently finished Atul Gawande's "Better" (highly recommended), which had a chapter on CF. Even today, a well treated CF patient living to such an age would be remarkable; when this woman was born living to 20 would be lucky. Clearly she either has a very modest deficit or some interesting modifier or such (late onset?) which allowed her to live to this age.

Now, if this patient didn't have any CF in her family, would one test for this? Probably not. But thinking more broadly, will this scenario be repeated frequently in the future when complete genome sequencing becomes a routine part of large numbers of medical files? Clearly we will have many "variants of unknown significance", but will we also find many cases of occult (hidden) genetic disease in which a patient shows clinical symptoms (but perhaps barely so). Having a sensitive and definitive phenotypic test will assist this greatly; showing excess saltiness of sweat is pretty clear.

From a clinical standpoint, many of these patients may be confusing -- if someone is nearly asymptomatic should they be treated? But from a biology standpoint, they should prove very informative by helping us define the biological thresholds of disease or by uncovering modifiers. Even more enticing would be the very small chance of finding examples of partial complementation -- cases where two defective alleles somehow work together to generate enough function. One example I've thought of (admittedly a bit far-fetched, but not total science fiction) would be two alleles which each produce a protein subject to instability but when heterodimerized stabilize the protein just enough.


Nash said...

I suppose these patients could be thought of as what the yeast geneticists call "suppressor mutants" . Things like 454 sequencing of these patients, among other studies will not only elucidate the naure of the disease but will clearly pinpoint a possible cure/treatment

Steve Murphy MD said...

@Nash and @Keith

Yes, I agree. We will see more people act on VUS. In her case she had an intronic mutation and a standard Del508.

She had a clinical phenotype: Bronchiectasis with what was "presumed" to be COPD in a nonsmoker, Alpha 1 AT negative. AND the family history. Which is why we pursued anything here. She now takes Hypertonic saline and is covered for pseudomonas and classic CF bacteria whenever she has a relapse, which BTW, when we started saline, she has not had........

A totally different treatment from COPD......