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Saturday, May 12, 2012

Is Gene FIG4 Responsible?


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.


Start IGV, download Stacy's copy of  FIG4, and type in FIG4 into the address bar at the top as shown in this previous post.

As in the last post, we will assemble a list of known causes of CMT4 within the FIG4 gene. We will examine each CMT4 causing mutation in Stacy's FIG4. I will take a screenshot of anything of interest and discuss potential ramifications.

We have excluded known FGD4 causal mutations.
  1. FGD4  -- 5 mutations cause CMT4
  2. FIG4 -- 20 mutations cause CMT4 Download Stacy's FIG4
  3. GDAP1 -- 18 mutations cause CMT4
  4. MTMR2 -- 10 mutations cause CMT4
  5. PRX -- 2 mutations cause CMT4
  6. SBF2 -- 5 mutations cause CMT4
  7. SH3TC2 - 19 mutations cause CMT4

Below is the list of the 20 known FIG4 causal mutations for CMT4 that we will analyze.

Mutations causing CMT4 in the FIG4 gene.
Number Codon Mutation
1 17 Leu17Pro
2 41 Ile41Thr
4 98 Phe98fs
5 183 Arg183X
7 253 Gly253fs
10 302 Glu302Lys
12 348 Asp348fs
13 381 Arg381X
17 559 Lys559X
19 823 Gln823X
20 899 Arg899X

There are a lot of mutations to check in this gene. The previous post explains how to navigate to each codon and search for any mutations that don't match the reference sequence. I highly encourage you to download Stacy's FIG4 and manually inspect a few of these mutations yourself. I'm going to go through this list of 20 mutations and note anything of interest.


Below is a list of each mutation and the results of the visual examination.

  1. Codon 17 matches reference sequence
  2. Codon 41 matches reference
  3. Codon 97 matches reference
  4. Codon 98 matches reference
  5. Codon 183 matches reference
  6. Codon 252 matches reference
  7. Codon 253 matches reference
  8. Codon 262 matches reference
  9. Codon 276 matches reference
  10. Codon 302 matches reference
  11. Codon 347 matches reference
  12. Codon 348 matches reference
  13. Codon 381 matches reference
  14. Codon 382 matches reference
  15. Codon 457 matches reference
  16. Codon 555 matches reference
  17. Codon 559 matches reference
  18. Codon 662 matches reference
  19. Codon 823 matches reference
  20. Codon 899 matches reference


Stacy doesn't have any of the 20 known mutations causing CMT4 in the FIG4 gene. As I browsed through the gene, I noticed a few regions that don't match the reference genome. It's entirely possible that a previously unknown genetic cause of CMT4 is housed within Stacy's exome. In going after the low hanging fruit, it's best search known causes as a first pass. In terms of potential therapeutic intervention, I'm a bit torn as to whether it's best to have a known mutation causing a rare inherited disease or whether it's best to find a novel mutation. On one hand, having a known mutation allows one to benefit from previous research studies that characterize the disease causing mutation. On the other hand, one may be lucky as some previously uncharacterized mutations may lead to obvious experimental procedures that have a chance of alleviating symptoms.

In the next post, we will examine GDAP1 for CMT4 causing mutations...

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