A look at my whole genome sequencing results

[Hoopoe]

I have access to my own raw data and am looking through it slowly.

One of the interesting findings so far is a series of mutations in the HLA-DQB1 gene, and one in the HLA-DRB1 gene which are all associated with increased risk for multiple sclerosis.

PS: also many variants in HLA-DQA1.

I also have one of the IDO2 variants reported by Phair as potentially damaging (which is very common in the general population, so it doesn't really mean anything), and one that is a missense variant not reported by him.

 

[Hoopoe]

I also have a "likely pathogenic" variant expected to cause a nonfunctional protein in a gene involved in fatty acid oxidation, for which no population frequency data exists, and which has no entry on ClinVar. Sounds promising.

PS: but the associated disease has an autosomal-recessive inheritance pattern which means that this mutation might have no damaging effect, or only a small one. Maybe this is not the answer?

 

[Hoopoe]

Small update on the fatty acid oxidation mutation.

After applying a healthy dose of skepticism and doing some research, I think this a genuine finding, with a real impact on enzyme activity (I found a paper with a patient that had the same kind of heterozygous mutation where enzyme activity was measured). Whether it is actually behind certain symptoms in my family is a bit tricky to determine though. I really doubt this alone could explain my ME/CFS.

 

[merylg]

Did you get any analysis or panels that group relevant genes together into reports?

Things like Immunology, Neurology, Muscular Dystrophy, Connective Tissue Disorders, Periodic Fevers, Cardiology, Gastroenterology, Periodic Paralysis, Opthalmology, Mitochondrial Panel etc etc

I bought all these reports when on sale at reasonable cost. Some have been helpful, some not very helpful.

Some things I found on 23andme were validated by the WGS.

Worth looking into your heritage eg I have a lot of Irish heritage so am looking at Irish heritage diseases.

I also have some Sardinian heritage so looking at their heritage diseases.

Only got the heritage through 23andme plus records from own family history.

 

[Hoopoe]

Did you get any analysis or panels that group relevant genes together into reports?

I bought a month of access to an online tool that can do "gene panels". It is called gene.iobio

 

[Hoopoe]

Small update:

The fatty acid oxidation mutation found is in the gene corresponding to the disease "medium chain acyl-CoA dehydrogenase deficiency". As mentioned this is an autosomal recessive disease which would not be expected to manifest when only one of the two inherited genes is affected. Some people believe in the idea "synergistic heterozygosity" which says that a person can have inherited diseases if multiple genes affecting the same pathway have mutations (that individually would not be able to cause disease). The symptoms of this illness are poor fasting tolerance, low energy and episodes of hypoglycemia which fits very well. What does not fit is that this disease also causes episodes of life threatening metabolic decompensation, but that might be a question of severity. If I have this, it would also be the "late onset" form which is recognized to exist and may have a slightly different symptom profile. I also have a mutation in a similar gene that is involved in fatty acid oxidation of longer fatty acids but it's less clear if this mutation is pathogenic. The other mutation is almost certainly pathogenic.

In this study, some patients with only a heterozygous mutation had residual enzyme activity that is in the range where it is of some concern (according to what I've read, it's clearly not in the range of severe illness). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444485/

 

[Hoopoe]

Did you know that we all have a huge amount of genetic mutations? In some of my genes I have hundreds of mutations, in others just five or so. The difficulty is figuring out what these mutations do, and which ones are relevant to the problem we're trying to solve. We don't seem to know what the vast majority of mutations actually do. I'm also constantly seeing mutations which are not listed in databases. That might suggest they're very rare.

I'm mainly interested in finding out what is causing my poor fasting tolerance / episodes of hypoglycemia. This is very likely a genetic problem.

Some other interesting mutations:

My SC25A5 gene has three mutations that seems like they might lead to a nonfunctional protein. This protein exchanges ATP and ADP between cytosol and mitochondria. It's one of three proteins that have this function. I haven't figured out yet how to tell in this kind of situation if both copies of the gene are affected or just one. The allele frequency of these mutations is relatively high so these are maybe not particularly impactful, somehow.

SLC44A4 also looks interesting because it has a mutation that might affect phospholipid synthesis (relevant for ME/CFS according to recent research by Lipkin et al) and synthesis of acetylcholin.

SLC25A37 is another mitochondrial protein. There is a missense mutation. The function of this protein is iron import into mitochondria. The mutation is very rare and in and a highly conserved region. There is no data on what this mutation might be doing. It is however predicted to be benign by most prediction tools.

 

[Hoopoe]

I spoke to a neurologist who agreed with everything I said about the possibility of "medium chain acyl-CoA dehydrogenase deficiency". He believes it would show up on my muscle biopsy. I'm waiting for the results of that.

PS: and based on what I've read, this disease would not be able to explain significant functional impairment in daily life, unless the person had suffered from severe hypoglycemia at some point that caused irreparable damage. This would add to my diagnoses instead of replacing ME/CFS.

 

[Hoopoe]

Another interesting mutation in the PRKAG3 gene, although difficult to interpret and not clearly pathogenic.

The protein encoded by this gene is a regulatory subunit of the AMP-activated protein kinase (AMPK).

AMPK is an important energy-sensing enzyme that monitors cellular energy status.

Studies of the pig counterpart suggest that this subunit may play a key role in the regulation of energy metabolism in skeletal muscle.

 

[Hoopoe]

I found something that might be part of the genetics of ME/CFS or associated illnesses. The chance that this is important is probably low but it's still encouraging. We should be studying more families where people have ME/CFS and associated illnesses like POTS or orthostatic hypotension. I'm in contact with a researcher about this. The associated mutations are there, we just have to find them.

 

[Hoopoe]

Some genes have a large number of variants. For example my HLA-DQA1 gene has 1244 . Here the software highlights 17 of them as being of possible interest. None of these are probably doing anything significant. The HLA genes seem to be the among worst in terms of sheer number of mutations.



Other genes have very few or only a single variant, like for example my IGSF8 gene. The software flagged this because there's a frameshift mutation which is generally damaging. However not much is known about this gene.

I also had a blood test to rule out the possibility of antitrypsin deficiency as I had two potentially high impact mutations in the relevant gene, but my blood levels were high enough to avoid problems.