Bit of a shot in the dark on my part, but here goes: My daughter stopped walking about the time she was six. The disease began around the age of four. She's in a wheelchair full time. MRIs, EMGs, etc. are 'normal'; one doc said he could show her file to his students and they'd say she's 'normal'. We've eliminated ALS, CMT, CP, etc. To date we've stumped National Children's, Hopkins, USC, UCLA, St. Louis, and two separate teams at NIH as to what the heck happened and can it be fixed. NIH's best guess is that there's something in her exome - exactly what, they don't know.
So, I'm throwing an interesting case onto the table. Can't offer much more than that; and bragging rights at the bar.
Let me know what you need in the way of data and I'll see what I can get from NIH.
2 answers
I do not consider this question problematic, it is perfectly reasonable and justified in your situation.
It is clear that you are a very loving and resourceful father, and truly, I'm sure everyone here would be willing to aid you in any possible way to help your daughter.
Unfortunately, there is nothing anyone here can do without access to your daughter's medical records. If she does have a form of muscular dystrophy or motor neuropathy, and none of the labs you have mentioned caught it, it won't be one of the usual suspects... Assuming it is a variation in an unusual gene, then finding it is akin to finding a needle in a haystack... even if we had access to her full genome, your genome, your wife's genome, and your healthy daughter's, it could take years to validate the cause of her condition. I worked on motor neuropathy in a family where many children were born with the symptoms you described, but it still took us 3 years to find the causative variation in their DNA. We used not only the genome, but also all the medical observations noted by the paediatricians to make the haystack a little smaller. We also benefited from the fact that the immediate family was huge and over 20 people had their exome sequenced. So in all honesty, without a lot of data there isn't much we can do...
... which brings me to the point of consent. In order to know what you are giving away when you make public your genome, you have to be prepped by a clinician. To give it away without understanding what it is you are giving away becomes a huge legal problem.
For example, I know from a quick Google with the little data you provided here that your name is S, you live in .., V., and you like to ... Imagine what 3 billion bits of DNA could say - from each of your family members.
So it isn't possible I am afraid. We simply cannot ask you to provide the information we would need, and even then it would be unlikely to result in anything. However, putting forward your case to a genetics lab is a good idea. Technologies are always improving. The cost of exome sequencing has dropped like a stone. What was inconceivable 5 years ago is routine now. Rather than talking to us, it may be wise to go back to the NIH and ask if there are any more avenues to explore :)
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but did you sequence her exome at the end? Did you sequence your own genome and her mother's genome? (to detect "de-novo" mutations)
Raw sequence data in fastq / fastq.gz format. Were you and your wife sequenced too? Any idea what analyses have been carried out thus far? Variant calling? Any more specifics on your daughter stopping walking? (can she still attempt to walk i.e. muscle weakness / lack of muscle mass development?)
Sir:
Variant Calling is the process of identifying mutations from the sequencing experiment. Sometimes it's tricky. If they've already sequenced the three of your, we should assume they've already identified all the clear mutations in the affected daughter, which is all we could do too. The majority of mutations are classified as "who knows" because the majority of human genes are poorly understood medically.
The only path forward is to investigate every mutation in mice, which costs millions, or, the common solution is to find a second or a third family with the same symptoms and hope they have the same cause. You should join support groups for muscular problems and hope to join a group research study.
Reading all the posts, I almost feel there might be something outside the exomic regions, and if wouldn't be a first in medical history. however, this is a far shot and a whole genome sequencing can be extremely expensive. The famous $1000 dollars genome is theoretically available if you find a lab who has the machine(s) and can execute it (and runs tons of them). analysis can also be challenging, especially because, as karl mentioned, most of the mutations are unknown and the interpretation will be the problem. you would also have to re-sequence again yourself, wife and healthy daughter. so, as others already mention, I echo that a genetics lab with focus on muscular issues can be your best bet.
Sir...I/we really prize your effort, you are an exemplary dad for reaching out and looking for support even in a tricky field like bioinformatics, you are being a driver of a huge effort and it's more than admirable!! I do think there are still progresses that can be made on understanding what is happening to your daughter (after tackling all legal/ethical/technical problem) and I wish you the best of luck in finding the correct lab!
Questions:
Having VCF data would be huge. A BAM file is another plus, but I would start by looking at the variants.
How old is she now? Is the weakness primarily proximal or distal? You have checked for spinal muscular atrophy?
I am troubled by the ethics of this and am considering closing this question. It is very unlikely that the people commenting on this have a medical (as opposed to bioinformatics) background. Feel free to disagree if I've misrepresented anyone's background. Having worked with clinicians interpreting exome data, I would still argue that your best chance of success is engaging with the medical community.
I agree you Daniel, I'm not comfortable with those medical questions. I suggest we wait for some clarifications from sksvilich ?
Fair enough & understood. I stumbled across your site while searching for one of her docs. If anything, I have some great questions to ask next time we see NIH. Thank you all for the barrage of questions in such a short period of time.
I worked with rare disease exome data for 4 years, believe me I understand the needs of the families, I've been to conferences funded by efforts of patient groups. However this is still the release of identifiable data that has not been consented properly, and it just makes me a little nervous in that respect. You might want to check out Manuel Corpas' blog who has worked with his own family's genetic data: http://manuelcorpas.com/
I think the question is actually pertinent since he specifically asks:
whether then ppl comments range from medical to bioinformatics that's a different issue and I would suggest members with further comments to focus on the bioinformatics part of the question
if my daughter (which I don't have) had a similar issue my first thought would be to reach out to as many ppl as I can to get the right answer or, in this case, to understand what bioinformatic approach can be taken or what's needed to analyze her mutational load. and, on the bioinformatics component, I think this is the right place to ask :)
I disagree. The OP is already engaged with the medical community. I think the subject line should be along the lines of "Can you find any leads on this case?", because like you said most of us aren't qualified to provide an official diagnosis, but I work on a team that saved a child's life through evaluation of exome-seq data, and none of us had MDs when we found and researched the critical variant which informed the proper treatment of the life-threatening disorder.
There is a lot of talent and knowledge here, and it's possible we can do some good.
And why is that a problem? As long as there is a disclaimer that the analysis CANNOT be by ANY MEANS used to guide medical decisions and that the authors cannot take any responsibility because of their lack of training/certification, it's fine with me. Yes, risk of misinterpretation is very high, but that in my opinion shouldn't oppress free access to the information. (If this happened in my family, you can bet I would want to take a look at those fastq files.)
This is why: http://www.ncbi.nlm.nih.gov/books/NBK132157/
Are we able to get informed consent from sksvilich?
What constitutes informed consent for this group?
How broadly will the data be shared?
If you share it here you need to understand you effectively turned the data public. That is why I am asking Daniel Swan whether you can even give informed consent on this level.
We're internet strangers. You'd effectively be giving your family history medical records freely to the world. Right now there's no danger, because we can't see anything obvious, but once the data is out there, you're vulnerable forever. Have you seen the movie GATTACA? Imagine, in twenty years, we can better understand the genomic data, and your older daughter is discriminated against, prevented from joining a mission to Mars because this data you naively released shows she's got some chance of some disease. It also releases probabilistic information on your siblings and parents and cousins. Your wife's brother has a good chance to carry the same chance of Alzheimers we see in her genome, for example, (and brings a lawsuit). It's irresponsible to release that data.
Hello sksvilich!
We believe that this post does not fit the main topic of this site.
This thread was deleted. I think it would be better to keep this discussion and to just "close it" (?)
For this reason we have closed your question. This allows us to keep the site focused on the topics that the community can help with.
If you disagree please tell us why in a reply below, we'll be happy to talk about it.
Cheers!
May be this post doesn't fit to the main topic of this site but it perfectly fits to the main intention of Bioinformatics in terms of Medical/Diagnostic applications. In our inst. we highly use NGS with a concept of 'Accelerating Genomics for Health'. May be some one can direct him to some center which uses NGS for clinical/medical applications in his respective area. If he carry answers for questions posted by @Dan D, he might find some solution.
I think the question fits perfectly the topic of the site. I agree that this question indicates the path of future medicine.
It can be rephrased as: how can bioinformatics help to diagnose a rare genetic disorder and which data would be required. This was formulated in layman terms, but I don't remember we have a rule forbidding a non-bioinformatician to post. The question raised concerns on the ethics of data disclosure, and legal concerns towards the implications of giving health related advice.
One might pose the question whether bioinformaticians or geneticists are the best audience to ask, but then the question arises who else can design and analyze such experiments?
I have changed the title because the original title was a bit misleading
This is nice article, covering also "who owns the data" issue: http://www.nature.com/nbt/journal/v33/n9/full/nbt.3340.html