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...

• Arg954X (Known CMT4C causal mutation)
• Gly843Glu (Potential Novel CMT4C causal mutation)

These two mutations are on different haplotype blocks, making it very likely that they are compound heterozygotes.

Visualization of the Likely Compound Heterozygotes

***Note:  I "flipped the strand" on the reference genome since SH3TC2 is on the reverse strand. This means we have to read each codon in reverse and we must also reverse complement Stacy's reads. This means that the "A" you see below should be considered a "T". 

Here is Stacy's Arg954X mutation:

Here is Stacy's Gly843Glu mutation:

Gly843Glu is Likely a Novel CMT4C Causing Mutation

After some digging around, I found that Arg954X is a known recessive CMT4C causal mutation. Since Gly843Glu is on the other haplotype block, it is likely disrupting function on the second copy of the gene, leading to two loss of function mutations (one in each copy of the gene). However, Gly843Glu is not showing up in any database I have found nor in MedLine searches as a known CMT4C causal mutation. It is very likely that Gly843Glu is a novel recessive CMT4C causal mutation. I say "very likely" because although this appears to be (by far) the most probable explanation for Stacy's CMT4, I intend to find another individual with CMT4 who is missing all known causal variants, but is homozygous for Gly843Glu.

Discussion

I am extremely grateful for Brad Chapman's assistance as well as for 23andMe's commitment to giving people access to their own genomes. We can now be almost 100% sure that Stacy's compound heterozygous mutations have been identified. I would like to point out that this process was a lot cheaper than the $3000 that Stacy was going to be charged out of pocket by doing this via a hospital and we learned of the causal mutation 11 days after getting her exome from 23andMe. We not only know more about her disease, but can also examine thousands of other genes as well. I will go through more details in future blog posts about how to replicate this entire process that has led to these findings. I intend to be thorough, so I will continue to search for anything suspicious in any of the known CMT causal genes as well finish inspecting the remaining known CMT4 causal mutations in Stacy's exome. I also intend to add citations and tidy up a lot of the work that has been done. My goal was to move quickly, but I can now add some polish now that I believe the causal mutations have been identified. I wilI also discuss the next steps in validating the potentially novel causal CMT4C mutation Gly843Glu as well as researching the pathophysiological effects of these mutations.