Stacy Project
Thursday, May 24, 2012
Final Set of Mutations
The previous post has identified what I believe to be the CMT4 causal mutations. For the sake of being thorough, I will wrap up the genetics analysis by checking all CMT causal mutations in this one single post. It will be constantly updated until I have covered every single disease associated mutation in every single CMT causal gene. This post is going to be long, so feel free to ignore it. I'm just consolidating all of the mutations on CMT causal genes and making them public in the spirit of this blog. Note: not all of the mutations I will check cause CMT. Some mutations on CMT causal genes cause different diseases (e.g. Macular Degeneration).
Friday, May 18, 2012
Likely Cause of CMT4 Identified: SH3TC2
Extremely Likely Cause for CMT4 Identified
I received an email from Brad Chapman who has an awesome blog that explains how to deal with next-generation sequencing data. He generously offered his assistance in tracking down the CMT4 causal variant(s) in Stacy. As opposed to manually inspecting each known causal variant, he proposed scanning all low frequency mutations within known causal genes. Thanks to his help, we now know that Stacy has two mutations in the known CMT4 gene SH3TC2 that are so rare, they never occur in the 1000 genomes dataset. These two mutations are...Wednesday, May 16, 2012
Is MTMR2 Causing CMT4?
Commentary
A lot has happened over the weekend. I've received some very encouraging e-mails as more people find out about this project. I want to thank you all for your interest. I wasn't sure what to expect, but my hope is still to make this as accessible and easy as possible to remove some of the "aura of mystery" surrounding genetic analysis. We live in an era when we can go from receiving a digital file through the internet to literally searching for the genetic basis of a mendelian disease in a loved one. While manually inspecting variants should not replace expert analysis, it can only help. In fact, Stacy initially went to the hospital to determine the genetic cause of her disease. She went to the hospital and they told us that they would check only known genetic causes for CMT4 for ~$3,000 and that insurance wouldn't cover the cost. This is about the same time that I heard 23andMe was about to launch a pilot for sequencing 80x exomes for $1000. Stacy decided to wait for this and then have me personally analyze her exome. This blog is the result of that decision. We are on the brink of an era when full genome sequences for all of us will be common place. It is my hope that in the future, people will not have to wonder what genetic mutation is causing their mendelian disease. Even if the result is not currently actionable, they will at the very least know what technological advances need to be made before a symptom decreasing therapeutic intervention is developed.Sunday, May 13, 2012
Is GDAP1 Causing CMT4?
Background
We are moving on to the 3rd gene to test for CMT4 causing mutations. In the last two posts, we investigated genes FGD4 and FIG4. We found no known CMT4 causing mutations in Stacy's exome. We still have 4 out of 7 genes to check. As we move down the list, the chance that Stacy either was misdiagnosed or has a novel mutation causing CMT4 increases. However, we won't know for sure until we exhaust all known mutations. Here, we check GDAP1 for CMT4 causing mutations in Stacy's exome.Saturday, May 12, 2012
Is Gene FIG4 Responsible?
Background
In the last post, we investigated gene FGD4 and found no known CMT4 causing mutations in Stacy's exome. It was the first of 7 genes we plan to check. Although it would have been absolutely amazing to have found something in the very first gene we checked, there are plenty of mutations left to check. This time we will be investigating gene FIG4. Please review the last post in order to follow along in this analysis.Friday, May 11, 2012
The FGD4 gene
Background
In the last post, I covered how to visualize a bam file and find for mutations. In this case, we're calling anything that doesn't match the reference sequence a mutation.You can consider the "reference" sequence to roughly represent the DNA that the majority of people have. Not matching the reference sequence doesn't mean it's necessarily bad. All of us have millions of locations that will not match the reference sequence. However, not matching the reference sequence in a region known to cause a rare disease in someone who has said disease is a cause for further investigation.
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