Hi everyone, I have recently been diagnosed with EM but I have been showing signs of it for years. I would like to be tested for the SCN9A mutation but my doctor doesn’t seem to know much about it. Has anyone used 23 and me to check for this? If so did it work? I’m not sure how accurate this would be.
My docs told me they never recommend 23andme. That it can be misinterpreted by consumers eg if they use promethease to analyze.
What would be the best I think is whole exome sequencing which would be done by a genetics department at a hospital. However this is not usually covered by insurance (my insurance didn’t cover). But they would be able to look at de novo mutations in the sodium channels and other related genes like thermoTRP’s.
My neuro used Invitae to test for known small fiber neuropathy mutations, which includes SCN9A. I think if a doctor requests it, the test is free or nearly free.
I did use 23andme and promethease 
I think there is a SNP that’s relatively common called [rs6746030] that people interpret as the cause of their EM (has been associated with decreased pain thresholds and even non-EM pain conditions like osteoarthritis). But, many people have this SNP and are fine, and I wonder this could lead to possibly neglecting other contributing causes.
I’m not sure whether promethease gives you results on all known EM mutations (it basically connects you to whatever is in SNPedia). I can remember at least 1 mutation they pulled out for you, but there are ~20 mutations now associated w/ EM. 23andme (at least when I did it) will just give the raw data and so most people need another service (like promethease, but there are others) to analyze.
I’d be interested in others’ experiences with promethease or other raw data-analyzing services
here’s a pic of the SCN9A mutations as well as the SNP I mentioned:
Definitely agree with @standing_cat to avoid 23andme for something like this. Exome sequencing is your best bet and the most accurate and scientific. I recently had my whole exome sequenced by GeneDx through Northwestern Medicine (it took like 6 months from start to finish) and nothing was found which was good since I have improved greatly since. They had a specific panel they tested for and it was all clean but it was specific for my problems, which 23andme is not. The rate that I was given was high, like $2000, but since I was hardly making any money I was able to have my rate reduced to $40 for the whole thing via GeneDx by filling out a qualification form, not through my insurance. This might be something to look into with your doc if you are serious about getting the testing done. Of note, I had SCN9A testing done a year prior at University of Chicago and they just tested for the 3 known sodium channel mutation but the exome testing covered a whole neuropathy, autoimmune, and dysautonomia panel among many other things in addition to a second round of SCN9A testing. Basically, exome sequencing is your best bet to find a genetic anomaly due to the broad yet individually tailored qualities of the test.
My daughter has had Symptoms of him for the last five years. We looked at getting testing through UCLA a few years back but because of the cost could not do it. Just in the last six months we revisited it and threw UCLA found a private genetics testing facility that was very curious about doing the testing for us. They tested my daughter myself my husband and found out that she has a familial mutation in her SCN9A from me. The only reason we did this testing was to make sure that she did not have an auto immune disorder or something else that was causing the EM symptoms. It has brought some peace in knowing this information. Now we can proceed with pain management to figure out how to care for her.
Hope this help,
Bonnie Worthen
Can I ask if you have EM symptoms?
Hope pain management is helpful.
Yes, I have always had mild symptoms, but nothing close to the over the top symptoms my daughter has. She test a spinal stimulation and are now waiting for final approval for permanent one.
Thanks!
Bonnie
Let us know how the spinal stim goes! What parts of the body is it supposed to cover? I do not know much about spinal stims.
I hope it goes well.
My dad has mild symptoms (daily red ear syndrome symptoms) but like your family, my symptoms are much more pronounced / disabling. I can see how knowing about a mutation would give you some sense of peace in this whole roller coaster.
Hello
I used 23 and me, then sent my raw data to promethease, I had two SCN9A mutations which are the : [rs6746030] (https://www.snpedia.com/index.php/rs6746030)(A;G)
reported to influence perception of pain
rs6746030 is a SNP in the sodium channel Nav1.7 SCN9A gene. In five cohorts tested, totaling 1,277 individuals, the rarer rs6746030(A) allele was associated with increased pain (p=0.0001).
ClinVar Non-pathogenic Primary erythromelalgia Hereditary sensory and autonomic neuropathy type IIA Generalized epilepsy with febrile seizures plus
.
And The second one was : rs41268673(G;G)
common in clinvar
ClinVar Other Primary erythromelalgia not specified Inherited Erythromelalgia Hereditary sensory and autonomic neuropathy type IIA Generalized epilepsy with febrile seizures plus
I took my reports from Promethease to my Hematologist who read all of it, took my symptoms, where he declared I have EM, I also took all the information to my family doctor who did her research on all of this and also diagnosed EM.
hope this helps
I’m so sorry to hear about your dad. This is a terrible disorder and a half. It is hard watching someone you love in pain 24/7.
She is having it in her upper body it will cover her hands, and face. She has EM in all her extremities face ears and legs and feet. The first round they are doing her upper body. If it responds the way they’re hoping they are then thinking they will do one for her legs and feet. Our fingers are crossed and we’re sending up prayers that it does go well. I will for sure follow up with you and let you know how it goes.
~ Bonnie
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What makes you think you have a mutation here?
From my Hematologist/Oncologist, here is what they found from my genes,
| Reference | Rs41268673(G;G) |
|---|---|
| Significance | |
| Disease | Primary erythromelalgia not specified, Inherited Erythromelalgia Generalized epilepsy with febrile seizures plus Hereditary sensory and autonomic neuropathy t |
| Variation | info |
| Gene SCN9A | |
| CLNDBN | Primary erythromelalgia not specified Inherited Erythromelalgia Generalized epilepsy with febrile seizures plus, type 7 Hereditary sensory and autonomic neuropathy type IIA |
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The homozygous G which you have is the more common genotype (99%+).
-
The rs6746030(A;G) result means you have one A allele and this happens in about 10% of the population (way more common than EM)
As per Waxman: “We screened the family members and the ethnically matched control samples using restriction enzyme analysis to determine whether R1150W segregates with the disease phenotype … Therefore, R1150W substitution reflects a low-frequency allele, which may not contribute to the disease phenotype.”
(R1150 W refers to the rs6746030G->A allele change)
edited to also add this: " The variant R1150>W was initially identified as causal mutation for primary erythromelalgia, but was subsequently found to have minor allele (T) frequency of 10% and is no longer considered as a causal mutation. Interestingly, a recent study indicated that the minor allele of R1150>W was significantly associated with the increased pain perception.[27] We did not find any of our patients with erythromelalgia with this polymorphism, but two of our six patients with CIP (congenital insensitivity to pain) carried its minor allele, which is conflicting with the notion of increased pain sensation. Our cohort is not large enough for association study, but our results emphasised the complexity of the genetic factors involved in the pain-related disorders, and the pain perception-altering mechanism of R>1150W needs further investigation."
I am sorry to hear about your daughter but the peace of knowing what is causing the pain is something at least. Has she tried any sodium channel blockers? They have been shown to provide relief in SCN9A mutations and when they work, they really really work. IV lidocaine or mexiletine would be something to consider giving a go.
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I made a little summary of what 23andme => Promethease can tell you about SCN9A.
(I haven’t double-checked this)
“common in clinvar” => you have the most common genotype.
rs4369876: see SNPedia.
rs200945460: “variant”. Reduced neurite length in vitro (Waxman). I720K
rs80356468: pathogenic. 2 pubs I136V
rs4438497: 1 pub on dental carries => not relevant.
rs182650126: Ile739Val. Linked to paroxysmal itch, SFN with severe dysautonomia, DRG excitability with sympathetic cervical ganglion autonomic neuronal hypo excitability
rs71428908: Ile228Met. Varying phenotypes. “variant” linked to impaired regeneration of neurons, reduced neurite length, increased excitability of DRG and trigeminal neurons in culture.
rs41268673: P610T. Initially found as causal (IEM), but now doubtful.
rs80356473: Leu823Arg. Japanese EM case, pathogenic.
rs6746030: R1150W = many association studies, some conflicting. Initially thought to be causal mutation for EM, but no longer considered causal as 10% of population is heterozygous. In particular, several CIP (congenital insensitivity to pain) patients have this variant. Waxman showed however that, in culture, this variant will increase firing of DRG and “may influence susceptibility to pain.” It seems Waxman ran into this variant when he was studying an inherited EM mutation (causal) within a family, and noticed some of the family members had this SNP (including non-EM members) and some did not.
SCN9A is considered to be a highly polymorphic gene. 120+ coding non-synonymous variants, 70+ mutations with various phenotypes.
Waxman looked at 28 people with idiopathic SFN, and found novel mutations in 8 of them, rendering DRG hyper excitable.
The most important mutations in current genetic research are: F1449V, L858F, L858H A863P, S241T, N395K, I136V, V1316A, G616R, G856D, I848T, I234T, and F216S.
tldr - It doesn’t look like doing this will be able to tell you much. I know more mutations / variants seem to be discussed in the EM literature than what is reported with 23andme / promethease (this may change in future). I am concerned people do this out of desperation for answers, and end up misinterpreting results.
I was tested and was negative and now I am fighting a $10,000 bill from insurance!
Yikes! That’s terrible. Since all EM treatments are off label and there is little medical benefit to genetic testing at this time, members should get prior authorization from their insurance company before pursuing it. The test could be deemed not medically necessary and/or uncovered by the policy.
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Bonnie -
Hope your daughter is doing ok. How is it going w/ the process of spinal cord stimulation?
Can I ask - where did she do her trial? (what level in her spine) Thanks.
She is ok thanks for asking! The implant was done at the top of her spine to help with her hands and arms. We praise God For that. It has helped and we are happy for just a bit of relief. We have tried all the Medications over the last five years. We now have to figure out how to help her live some as she walk with EM. My heart breaks for her and other with EM. I am not sure if it is better to not have a life and get EM or have had a life and it cut off.
She had been at UCLA for over the last three years and we have had great doctors there! It is great to have all her records and doctors in the same place.
Sending happy thoughts your way.
Bonnie
Thanks Bonnie + merry Christmas. Doctors at Stanford are open to trialling a spinal stim at C2 for my face/ears but acknowledge this high up is comparatively more risky. Was curious if hers was that high, but if it was for arms/hands it probably wasn’t.
Glad it has helped her.
Here is a 2015 table listing of PE associated mutations
https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0347-1/tables/1
(Note they do not list the common R1150W SNP)