Anyone interested in personal genomics should hunt down the new Nature (available online at the moment) and read the story of Hugh Rienhoff, whose third child (a daughter) was born with a still mysterious set of symptoms. Since her birth he has been bouncing around trying to get a diagnosis for her condition which resembles Marfan's and a similar disorder called Loeys–Dietz.
Rienhoff was trained as a physician under Victor McKusick and helped start a genomics firm (DNA Sciences), so he was a bit primed for this. Remarkably, he has apparently set up his own PCR laboratory in his house so he can perform targeted sequencing of candidate genes from his daughter's DNA -- using an unnamed contract research house. Alas, none of these searches have yet turned anything up.
Because of the similarity of his daughter's symptoms to the other two syndromes & because both of these syndromes involve TGF-beta signalling, as well as the well characterized role of TGF-beta signalling in muscle development & his daughter's muscular problems, Rienhoff & her doctor recently decided to put the child on a high blood pressure medication which is suggested to reduce TGF-beta signalling and to help in a mouse Marfan's model.
The story is a good illustration of the promise -- and the complications -- of cheap DNA sequencing to identify the causes of rare diseases. Small scale targeted sequencing hasn't worked out -- but given the large number of genes known to be involved in TGF-beta signalling the odds were never wonderful. Perhaps a full genome scan, or targeted resequencing using one of the new array-based capture schemes, might find a strong candidate mutation -- some of the other TGF-beta related syndromes are dominants, so perhaps this will be too & comparing the daughter's scan to the parents will single out the mutation. But, the results might be inconclusive -- no strong candidates. Or, perhaps a candidate is found because it is a de-novo mutation in the child & is likely to have a major effect (non-synonymous substitution, truncation mutant, etc), but in an utterly unstudied gene. At least that's something to go on, but not much.
The article touches on how patients with unusual clusters of symptoms often get lumped into 'dustbin' categories, syndromes whose common thread is an inability to assign the patients to another category. Personal genomics may be quite useful for cutting down on such diagnoses, as the genetic data may sometimes provide the compass to guide through the morass of symptoms. On the other hand, there will probably be whole new bins of genetic syndromes -- 'polymorphism in X with skeletal defects' -- again, it is something to go on, but they are almost guaranteed to pile up much faster than the experiments to sort them out can be run.
After reading the article, I can't help but hope that his daughter gets into one of the big sequencing programs, such as the recently announced Venter center 10K genome effort. There will be a lot to be gained by finding out the ordinary variation which makes each one of us different, but there should also be a bunch of slots reserved for patients for whom sequence results might, if they are lucky, give them some new options in life.
4 comments:
SO how about the ethical aspects of the case? Do you think some concerns are warranted?
As a parent myself, I know the difficulty of making decisions when they concern the welfare of our child. The father here has made a difficult choice in a difficult situation.
I think only if an overwhelming majority of experts rejected a course of action would I criticize a parent's choice of treatment options; the choice he has made is not clear-cut right, but nor is it clear-cut wrong.
Two short comments. I did find something -- a variant in the 3'untranslated region of the ACVR1B gene. I do not yet know if it carried by my wife or not.
Regarding therapy, there are always ethical concerns for every medical intervention, diagnostic or therapeutic. It is a risk:reward calculation individual to each patient or their protector in conjunction with the attending physician. The treatment is generally very safe and well tolerated and has been used in literally millions of patients. The disease on the other hand could involve irreversible damage to her vascular system. The choice seems clear. Of course as father I am not the doctor of record -- other physicians felt treatment was worthwhile.
I do hope that she and her two parents can be sequenced. A trio of transcriptomes or genome sequences would be very revealing.
Thanks for the correction.
As a parent myself, albeit having never faced nearly so difficult a decision, I wouldn't begin to question your decision -- I'm sure you've thought long & hard about it and talked yourself every which way on the route to it.
Best of luck to you & your daughter.
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