Options for genetic testing

Jonathan Edwards said:
I agree with @Kitty. If the ordinary blood test do not show anything, genetic testing will tell you nothing. Genetic tests might tell you why your blood tests are abnormal, if they are, but if they are normal then the genetics will be irrelevant. Genes can only have an effect through the chemistry that ordinary diagnostic tests assess.
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Would this still be your answer now, 5 years on, @Jonathan Edwards ?
Or would you say have there now been enough / any advances in research / understanding that would mean you'd give a different answer today?

I'm thinking specifically about if there are conditions / diseases / illnesses (whatever the correct word or words are!) that can be picked up through genetic sequencing (not necessarily 23 And Me specifically), but that would not be easily found on the "standard" set of blood tests that would (ideally) be run today for someone with M.E/CFS presentation.
 
I think, given the complexity of many genetic associations with disease, the difficulty isn't in the genetic testing, but in finding someone who can usefully interpret the resulting data. And, even if you do find someone with useful expertise, that expertise probably only covers a small number of possible conditions.

For example, in this thread, we discussed a currently free testing service for muscular dystrophies, which is part of a research programme:
Facioscapulohumeral Dystrophy (FSHD)
 
My daughter is waiting to see a neurologist to find out whether she has a particular genetic condition called myotonia congenita. It seems likely that she has it, or something in the same area (non-dystrophic myotonias), but the proper medically recognised genetic testing that is available has to be ordered by a specialist or genetic counsellor, and the wait for that is going to be long.

Is there any direct-to-consumer test that would give an answer in the meantime? She realises it could not be used for diagnosis, and that it might be lower quality than the testing she will eventually get. It's just the "not knowing" that is getting to her.

I'm guessing the answer is no but it's hard to watch her sitting at home, unwell, waiting yet again for help with another rare condition that could be effectively medicated if someone would let us pay for a couple of genes to be tested now. Although I suppose the medication would have to wait for the official diagnosis.
 
Ken Turnbull said:
Is there any direct-to-consumer test that would give an answer in the meantime?
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I know it's not what you want to hear, but no.

It must be incredibly hard for her, and for you as a parent, but maybe look at it this way: most direct-to-consumer tests were set up with the aim of profiting from people's genetic data, not to advance diagnosis or treatment.

There's no one-size-fits-all screening panel because they need to look in high resolution at the relevant locations. From what I understand, to do work that detailed on a whole genome would be a bit like using a microscope to search a city for the restaurant you want to visit.

Your daughter would be giving up control of her most personal information—and some of that of her close relatives—without even knowing what's going to be happen to it. She won't get a reliable answer, or any medication, so there's no benefit for her.

Could she maybe get support from online forums for the condition she's suspected of having? There must be lots of others who've endured the same frustrating wait, and sometimes just knowing that other people understand genuinely helps. People come here knowing there are no answers for ME/CFS (yet, anyway!), but it reinforces that they're not suffering alone. There's always someone to say "I hear you, and I'm thinking about you".

I'm really sorry she's gong through this, and I hope she doesn't have to wait too long.
 
@Ken Turnbull, perhaps your daughter could track down a myotonia congenita researcher and ask them if there are any genetics research studies underway? Someone might be doing similar work to that done by the FSHD lab I mentioned above, but for non-dystrophic myotonias. In fact, the FSHD researcher might be able to suggest someone to contact.
 
For doctors there is a screening panel they can order. You need the specialist to choose the right selection of panels in case it is not the diagnosis you mention, but one very similar.

You can do a screening by ordering WGS yourself and then using an open source tool such as gene.iobio to screen for the condition phenotype and the associated genes. But for 99% of people it is best left to the experts to run the right tests as it is a complicated analysis to learn from scratch. And at the end of the day the depth of the genetic reading is much deeper with the screening panels, so that would need to be run anyway.

I checked my WGS data on gene.iobio against the myotonia congenita phenotype. It highlighted that I am heterozygous for a missense on SCN7A - the 14th gene listed on the myotonia congenita phenotype. But that doesn't mean I have it. In fact, SCN7A is more likely to be associated with neuropathy, and then again only if I were homozygous for it. So as you can see even if you order your own WGS it is still very difficult to use and understand. That's why we pay the experts.

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According to a gene site (link) CLCN1 is the main gene of interest and I don't have a variant of that. And that site said there are a lot of tests a neurologist can run as well which may be needed.

Just to add, I have a family member who is very ill too. I ordered them a WGS testing service in 2023. The kit was sent to my family member who provided the spit and sent off the tube. They never got their WGS data or a refund despite an inordinate number of complaints. There are some dodgy players in this field.
 
@Kitty , thank you for the thoughtful reply. I joined a couple of support groups on Facebook (my daughter doesn't have a Facebook account because she says it is too annoying) and I posted a couple of questions and comments.

Unfortunately, one of the key people on one of the groups made a statement that it was not her "intuition" that my daughter had myotonia congenita. Not sure why she would make such an unwise statement with no basis. My daughter is an avid reader and she's narrowed down the possibilities very well. There are not many conditions that can cause generalised muscle hypertrophy in a sedentary adult. She's also had testing to rule out other possibilities (acromegaly, excess androgens).

But I'm a grumpy, cynical old journalist and my daughter has pre-diagnosed herself correctly four times so far (she awards herself a Fauxbel Prize in Medicine each time), so we took it with a grain of salt.

So that group is not much help, although we have read through it and found some common ground with her symptoms. I also joined another group, who are much more friendly, but reading posts there made us realise it doesn't fit her symptoms very well. Too bad you can't choose which disease you have according to how balanced the support group is!

I do agree about the privacy and information-selling concerns with sending off your DNA to a commercial company.

We are on the cancellation list with the neurologist, so perhaps we will get in sooner. Fingers crossed.
 
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@wigglethemouse , it is complicated, isn't it. I'm sorry to hear that your family member never got their data or a refund.

I think the neurologist will order panels for myotonia congenita, other non-dystrophic myotonias, and perhaps myotonic dystrophy as well. And they will do an EMG, although mysteriously some patients with demonstrable myotonia symptoms have normal EMG readings. My daughter only has what might be myotonia first thing on getting out of bed, when she has trouble getting her legs moving. But I doubt he will turn up at the house to measure that!

If it does turn out to be genetic, then there will be the matter of who my daughter inherited it from. If from her mother's line, there are no implications as no close relatives left. If from my line, then there are a lot of people who would need to be alerted. This is because even people with no symptoms of myotonia congenita can be susceptible to a life-threatening reaction to certain general anesthetic procedures. So that will be quite a process.
 
Hutan said:
@Ken Turnbull, perhaps your daughter could track down a myotonia congenita researcher and ask them if there are any genetics research studies underway? Someone might be doing similar work to that done by the FSHD lab I mentioned above, but for non-dystrophic myotonias. In fact, the FSHD researcher might be able to suggest someone to contact.
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Yes, that is a good idea. I saw the FSHD study and clicked through to the website. What a valuable service to patients and research.

There seems to be a reasonable amount of myotonia congenita research ticking over, including existing drugs being tested for possible repurposing to use in myotonia. And it's comforting to see that there are about five or so current drugs for treating it. Always good to have a choice in case one drug proves ineffective or has unacceptable side effects.
 
And having said all that, the genetic testing may not give a clear answer. People sometimes find out that they have a variant of unknown significance on the myotonia congenita gene, and then have to wait until more research data comes in and that variant is "upgraded" to being diagnostic, if that's the right term.
 
From the paper:
In the modern era of gene therapy, a molecular diagnosis has the potential to change management and provide a cure. Thus, since the approval of voretigene neparvovec-rzyl, two programs began offering free-of-charge genetic testing panels for IRDs: ID your IRD through Invitae (San Francisco, CA, USA), sponsored by Spark Therapeutics (Philadelphia, PA, USA); and My Retina Tracker through Blueprint Genetics (BG), sponsored by the Foundation Fighting Blindness (Columbia, MD, USA). Both programs provide panel genetic testing for a pre-specified list of genes known to cause IRDs. Of note, these do not provide whole genome sequencing or whole exome sequencing. Previous studies have found that a genetic diagnosis has been possible in 25–78.8% of cases using a panel approach [4,5,6].

These testing programs offered by Invitae and BG are now widely used in clinical practice due to their ease of access and lack of direct cost to the patient, physician, or payor. Invitae and BG provide a report for each patient containing a list of mutations in genes known to cause IRDs and a determination of whether the patient’s phenotype can be explained by one of these variants. These reports are also amended by Invitae and BG, where previously identified variants of unknown significance (VUS) may be reclassified as pathogenic or benign based on further analysis. Unlike many medical tests in which the results are self-explanatory, interpretation of genetic testing results requires some expertise. Since the sponsored panels can be utilized by any ophthalmologist or optometrist, many providers who are not familiar with genetic testing rely entirely on the interpretation provided in the genetic testing report. It is not uncommon to see that some providers and patients assume VUS is a disease-causing mutation. The purpose of this study was to share our experience in utilizing sponsored IRD panel tests by Invitae and BG, compare their reporting patterns, and determine how later reclassification of variants, particularly VUS, may change the interpretation of the tests.
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That is helpful. Blueprint Genetics and Invitae seem to be doing a decent job, but finding a genetic mutation does not necessarily mean that a person has a disease, and a lot is still unknown. I'm not sure about the 'free-of-charge' - I'm pretty sure there are usually significant costs.

As BG states on their website, “Despite the international guidelines and principles, there is still significant inter-laboratory variation in classification of genetic variants”
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There were significant differences in the findings between the two labs.
e.g.
One patient in the Invitae group was a carrier for a gene (CLN8) that was not tested for in the BG panel. Two patients in the BG group had pathogenic mutations in MT-ATP6 and MT-ND1, which were not tested for in the Invitae panel, and one patient was a carrier in MMAHC, which was not tested for in the Invitae panel.
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examples of differences said:
This cohort had seven patients tested with both kits from Invitae and BG. Patient one had a clinical diagnosis of cone dystrophy, and the Invitae kit reported VUS in ARHGEF18, INPP5E, NPHP3, and SEMA4A; BG reported VUS in ARHGEF18 and SEMA4A. All four of these genes are included in both panels. Patient two had a clinical diagnosis of retinitis pigmentosa and the Invitae kit reported BBS10, CA4, and NPHP1 as VUS; BG reported RCBTB1 and CA4 as VUS. All four of these genes are included in both panels. Patient three had a clinical diagnosis of macular dystrophy, however, Invitae and BG reported different pathogenic variants. Invitae reported that this had a pathogenic deletion in CLN3, which is associated with autosomal recessive retinitis pigmentosa; BG also reported this CLN3 allele as pathogenic. However, BG reported this patient to have a pathogenic deletion in CRX, which has been associated with autosomal dominant retinitis pigmentosa. Interestingly, Invitae reported this CRX deletion as a VUS. The BG report stated this patient had positive genetic testing due to the CRX deletion. Instead, the Invitae report stated this patient was just a carrier for CLN3 due to its autosomal recessive inheritance pattern and there was no causative genetic diagnosis for the patient’s phenotype. Both CRX and CLN3 were included in both panels. Patient four had a clinical diagnosis of retinitis pigmentosa and Invitae reported this patient to have a pathogenic mutation in CLN8, which is associated with autosomal recessive retinitis pigmentosa; however, CLN8 is not included in the BG panel. BG reported a pathogenic mutation in VPS13B, which is associated with Cohen syndrome, but stated this mutation did not explain the patient’s phenotype....
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I expect the performance of the panels is improving all the time, and some will be more mature than others.

The difficulty for us of course is that it's hard to know what, if any, panels might be useful for suggesting missed diagnoses, and that we have little idea as yet what gene variants might be useful in the diagnosis of ME/CFS.

It's interesting to have a look at the services though, as perhaps there will be an ME/CFS susceptibility panel one day.
 
On Invitae:
The Lawyer Mag April 2024
They have had financial difficulties
Invitae filed for bankruptcy protection in February and seeks to reorganize its finances, including securing a buyer and addressing its $1.5 billion debt load. The company has stated that its equity shareholders are unlikely to receive any recovery from the bankruptcy proceedings.
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Reuters further reported that the legal controversy unfolds as Invitae faces financial difficulties exacerbated by aggressive expansion strategies, including 13 acquisitions from 2019 to 2021, significantly increasing its debt. The company has also been impacted by rising interest rates, intensified competition, and reduced demand for elective genetic testing services.
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So, it would be worth checking out the situation before committing large sums of money to them.
 
A member who has used Invitae says that they have been good at communication.

The member was able to get some genetic screening done for free. It seems that, in the US at least, Pharma companies sign agreements with the likes of Invitae and Blueprint Genetics to offer screening for free. The Pharma companies benefit when people are diagnosed as having a health condition that the company has a drug for.

For people who can get this screening done for free, getting some relevant panels done probably doesn't have a lot of downside. (Other than privacy issues related to giving your genetic information to a company.)

I think there's a potential research study here. A patient charity could promote a few of the free panels to their members, with a researcher reporting the group results. It would be interesting to know if any treatable conditions are picked up (e.g. missed diagnoses), and there's an outside chance of identifying variants relevant to ME/CFS. For example, if there was any overlap in the 115 variants picked up by the Zhang et al study and the gene panels of the testing companies, this would be an inexpensive way to try to replicate the findings.

Example of a report done for a member is attached.
 

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The example @Hutan shared above was for sponsored testing for the neuromuscular disorders panel. This seems to be the website link.
https://www.invitae.com/us/providers/test-catalog/test-03280
Sponsored testing
In addition to insurance and patient-pay billing options, this test is also available through a sponsored, no-charge testing program.

Detect Lysosomal Storage Disorders Sponsored Testing
Detect Muscular Dystrophy Sponsored Testing
Mission: Genome - Danon Disease Sponsored Testing Program
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The Invitae Comprehensive Neuromuscular Disorders Panel analyzes genes that are associated with hereditary neuromuscular conditions, including but not limited to muscular dystrophies, inherited myopathies, mitochondrial disorders, congenital myasthenic syndromes, and rhabdomyolysis.
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