6 ms·

> A doctor can't write a script for whole genome sequencing just to see what turns up - it will be rejected by insurance 100% of the time because that's going o

> A doctor can't write a script for whole genome sequencing just to see what turns up - it will be rejected by insurance 100% of the time because that's going outside the scope of standard practice. To be clear, doctors frequently requisition genetic tests for suspected conditions when the test is justifiable and actionable. If you are demonstrating symptoms of a specific condition and genetic testing can be part of the diagnostic process, you can generally get it covered and performed. However, getting a whole genome sequence and then scrolling through the results isn't as actionable as it sounds. You can do it yourself for under $500 if you really want. A lot of people have gone down this route and been surprised at how little signal you actually get out of the data, unless you have a rare and significant variation.

FollowingTheDao 4y ago
> To be clear, doctors frequently requisition genetic tests for suspected conditions. No, they do not. I have been fighting for this for 20 years. I ended up finding my own genetic issue (23andme) myself and they STILL do not care. They would rather let me rot on disability and homelessness.
- PragmaticPulp 4y ago
  Genetic testing for specific diagnosable and treatable conditions are extremely common in the medical world. For example, the BRCA gene test is commonly given to people with elevated familial risk of breast cancer. They do not go searching through entire genomes for any possible variant, though. > I ended up finding my own genetic issue (23andme) myself and they STILL do not care. They would rather let me rot on disability and homelessness. Your other comments said you diagnosed yourself with PNP deficiency. This is generally a fatal condition in infants and adolescence unless treated early with hematopoietic stem cell transplantation. I wouldn't rely on 23andMe's SNP analysis as a genetic diagnosis of anything, especially disorders which are fatal in adolescence. 23andMe has been known to mis-mark certain SNPs at various times in the past, and it's not guaranteed 100% accurate. Is it possible that you were a carrier, but not homogenous for the variant? The condition is autosomal recessive, meaning you would need to inherit flawed copies from both parents. Having a single bad copy could show up in 23andMe but would not indicate that you have the condition. To put it in perspective, the number of cases of PNP known to the literature in the entire world is less than 100.
  - FollowingTheDao 4y ago
    >Your other comments said you diagnosed yourself with PNP deficiency. This is generally a fatal condition in infants and adolescence unless treated early with hematopoietic stem cell transplantation. Just stop please. Why do you think I do not know what I am talking about? How long have you researched this gene and have you talked to people who are actively involved in researching this? Only certain p[polymorphisms are fatal for infants. There are plenty of us living with partial PNP deficiency. https://pubmed.ncbi.nlm.nih.gov/32695102/ https://pubmed.ncbi.nlm.nih.gov/32695102/ Conclusions: Patients with partial PNP deficiency can present in the third decade of life with mild-moderate immune abnormalities and typical development. Near-normal immunity might be achieved with relatively low PNP activity. > Is it possible that you were a carrier, but homogenous for the variant? There are many genetic alterations which do not manifest as disease unless you inherit a broken copy from both parents. I am homozygous for four variants known to effect T Cells. There is not only one polymorphism that can reduce enzyme activity, rs1049562 rs1049564 - https://www.researchgate.net/figure/Purine-nucleoside-phosphorylase-PNP-rs1049564-variant-enzyme-activity-and-mRNA_fig2_319408659 https://www.researchgate.net/figure/Purine-nucleoside-phosph... rs1713421 rs1760931
    - PragmaticPulp 4y ago
      If you truly suspect this, it's worth exploring something other than 23andMe. 23andMe is useful, but not known for accuracy. Even their datasets have known to include mislabeled SNPs in past years. > Only certain p[polymorphisms are fatal for infants. There are plenty of us living with partial PNP deficiency. > https://pubmed.ncbi.nlm.nih.gov/32695102/ https://pubmed.ncbi.nlm.nih.gov/32695102/ The finding in this paper is that partial PNP deficiency produced normal development in 2 out of 3 siblings and near-normal immune activity in the 3rd, despite having only 8-11% of the normal PNP activity. The takeaway is that partial PNP deficiency might, in some cases, present with only mild-moderate immune abnormalities or normal functioning.
      - FollowingTheDao 4y ago
        I had my genetics one by 23 and me twice once with the v4 chip, and again with v5 chip. I highly doubt that it would come up the same in both of those runs if there was any type of error. I really don’t understand why it went down plays 23 and me so much. Near normal immune function in the third person is not normal immune function. I am one of the people that are affected. Please don’t tell me my history and please don’t assume you know everything about what I’ve suffered through. I’m so tired of this attitude. When there’s no evidence for something people always seem to want to make it into nothing. When, in fact, if they actually studied it, they would find the evidence. But they don’t and people like me just suffer with immune deficiency and mental illness and nothing gets done.
- WFHRenaissance 4y ago
  Are you Canadian or something?
  - mb7733 4y ago
    They said they are in the US.
- astrange 4y ago
  23andme is not a medical-grade genetics test. Finding a very rare genetic mutation in it isn't convincing unless you get a specific test for it or do 1000x WGS.
  - FollowingTheDao 4y ago
    This is not true whatsoever in any way. It does not have to be “medical grade”. Whatever that means. I mean, are you saying they get their snips wrong constantly.? if so, that’s patently absurd because they went through the testing to assure this doesn’t happen. Or when it does happen, it doesn’t happen with the consistency over different chips.
    - astrange 4y ago
      Yes, they get individual SNPs wrong constantly and for rare results are especially inaccurate. https://journals.lww.com/oncology-times/fulltext/2021/07200/new_study_shows_the_inaccuracy_of_at_home_genetic.7.aspx https://journals.lww.com/oncology-times/fulltext/2021/07200/...
      - FollowingTheDao 4y ago
        Thet get it wrong consistently? Did you even read the study? No you didn’t. Because if you did, you would’ve read this. “Results Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. Conclusions SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.” The SNPs I have are not very rare. And why did the task it wrong twice? Exactly wrong twice, they got all four SNPs exactly wrong twice? If you wanna give me the money to get a full genome test please send it to me and I’ll prove you were wrong. Because I’m currently homeless and on disability trying to fucking fix whatever problem I have no one fucking cares about.
- atdrummond 4y ago
  May I ask where you are located, roughly? YMMV but I was given genetics tests for my leukaemia, polycythemia vera and Crohns. All were routine. I actually had more issues getting a thiopurine metabolites test ordered than I did with any of my genetic tests.
  - FollowingTheDao 4y ago
    I am in the US. My issue is that I was diagnosed with a mood disorder before anything else. So now, even though my white blood counts, never get above four, well, not until recently. They dismiss any other problems I have. Because I think it’s all because of my brain. It’s so idiotic I can’t stand it. I can’t have any other illness because I have a mental illness. I’ve been telling doctors about my low white blood cell count for a decade. Not one of them does further testing on it. I don’t know how to convince them or what to say , I think one of the problems is I take such good care of my health and so when they look at me I look fine. But it does not show how I feel inside and it does not show the fatigue I deal with. Yo, I want to say you’re lucky that you have leukemia because that’s easily spotted. but I’m one of those people with this borderline chronic health issue that they don’t wanna waste time on because I’m not actively dying. I’m just suffering my whole life.
    - atdrummond 4y ago
      It actually took years for my Leukaemia to be sorted, funnily enough, due to the impacts my autoimmune disease and medications had on my blood levels. I also was told for years I was faking my stomach pains until my leg nearly fell off due to a MRSA infection, which subsequently turned into a case of pyoderma gangrenosum. I was then finally diagnosed with Crohn’s disease. I will say there are some good doctors out there. My email is always open to HN readers if you want some help or advice here. Best of luck regardless.
- tsol 4y ago
  When it comes to obscure and unlikely illnesses, many doctors have a hard time entertaining the idea. They're taught when they hear hooves to think horses, not zebras. From stories I've heard it seems like it takes trying until you find a doctor open minded enough, or perhaps there's a doctor/researcher that specializes in this area you can reach out to. Not all doctors are the same, to some it's just a job but I'm certain there are some out there that would be okay with exploring that
  - FollowingTheDao 4y ago
    Real conversation I had with a doctor. Me: I am still sick; insomnia, anxiety, skin infections, GI Issues, Chronic Fatigue Doctors: Well the only thing wrong is your low WBC count. Me: Why is my WBC count low? Doctor: That's just normal for some people. Me: If is is normal why do you have a lower range? Doctor: Have you been talking with your psychiatrist and therapist? Me: Will they know more about why my white Blood Cell count is low? Doctor: But we just do not know why you feel so unwell. Me: Are there any more tests you can do? Doctor: Are you looking for something to be wrong with you? Me: What? Doctor: You tests are all normal so I ... Me: My tests are NOT normal, my WBC count is low, consistently, and I have reoccurring mild hyperkalemia. Doctor: What test would you like me to do? Me: ...
jauer 4y ago
Eh. Doing it yourself is a huge pain even when you get useful signal. I wish I could pay someone a few k$ to check results against literature and a list of things I think are weird with my body. ex. I have family history and symptoms of hypothyroidism. I've had 3 doctors test T4&TSH, then shrug and say everything is fine. My dad had a similar experience before landing on a doc who shrugged and said "let's just try the meds anyway and see what happens." I got WGS out of curiosity, annotated the VCF with REVL scores, and sorted by score. The first entry was a low-frequency (121 hits in TopMed) NR1D1 missense variant. I couldn't find any literature on that variant, so I looked at the downstream THRA impact and found papers that talked about disruption to thyroid signaling, and said that T4 & TSH would look normal, so you need to check T3/rT3. I bounce this off my endo and ask if she'll order a T3 & rT3 test. She won't because endo society guidelines says that rT3 tests aren't clinically useful. I order my own tests from a labcorp reseller. My T3 & rT3 results reflect what the papers saw, so I get grey market thyroxine. Screw up the dosing and get a day of racing heart. Fix dosing and hypothyroid symptoms went away. After this I find out that there's a whole community of people with normal T4 & TSH results, hypothyroid symptoms, and wonky T3/rT3. Also that there's some kind of culture clash between normal docs and functional medicine docs about this.</shrug> I shouldn't have to resort to days of messing with bioinformatics tooling, a week of reading papers, and questionable sourcing of meds to test something that any doc should have been able to deduce if they bothered to have some curiosity about how I could have those symptoms if their normal test came back normal :(
- phnofive 4y ago
  Great job sticking with it - it's not easy and it is lonely, but you did it.
- buildbot 4y ago
  BTW there is a tool for this, though you seem like you did well on your own - promethease https://www.promethease.com/ https://www.promethease.com/
- hallway_monitor 4y ago
  Maybe a better doctor could get you the medicine you need. The ideal solution is to make many prescription meds available over the counter since doctors are often useless or actively harmful though their ignorance and hubris.
nibbleshifter 4y ago
> You can do it yourself for under $500 if you really want. I'm interested in learning more about this. I'd fucking love to get my whole genome sequenced and be given the raw data.
- chromatin 4y ago
  https://nebula.org/whole-genome-sequencing-dna-test/ https://nebula.org/whole-genome-sequencing-dna-test/
strbean 4y ago
Quick plug for https://brcaexchange.org/ https://brcaexchange.org/ It's a database of known BRCA1 and BRCA2 variants with significance scores and links to clinical research. If you get results telling you that you have variants in those genes, look them up here (under the guidance of a genetic counselor, of course).

FollowingTheDao 4y ago

> To be clear, doctors frequently requisition genetic tests for suspected conditions. No, they do not. I have been fighting for this for 20 years. I ended up finding my own genetic issue (23andme) myself and they STILL do not care. They would rather let me rot on disability and homelessness.

PragmaticPulp 4y ago
Genetic testing for specific diagnosable and treatable conditions are extremely common in the medical world. For example, the BRCA gene test is commonly given to people with elevated familial risk of breast cancer. They do not go searching through entire genomes for any possible variant, though. > I ended up finding my own genetic issue (23andme) myself and they STILL do not care. They would rather let me rot on disability and homelessness. Your other comments said you diagnosed yourself with PNP deficiency. This is generally a fatal condition in infants and adolescence unless treated early with hematopoietic stem cell transplantation. I wouldn't rely on 23andMe's SNP analysis as a genetic diagnosis of anything, especially disorders which are fatal in adolescence. 23andMe has been known to mis-mark certain SNPs at various times in the past, and it's not guaranteed 100% accurate. Is it possible that you were a carrier, but not homogenous for the variant? The condition is autosomal recessive, meaning you would need to inherit flawed copies from both parents. Having a single bad copy could show up in 23andMe but would not indicate that you have the condition. To put it in perspective, the number of cases of PNP known to the literature in the entire world is less than 100.
- FollowingTheDao 4y ago
  >Your other comments said you diagnosed yourself with PNP deficiency. This is generally a fatal condition in infants and adolescence unless treated early with hematopoietic stem cell transplantation. Just stop please. Why do you think I do not know what I am talking about? How long have you researched this gene and have you talked to people who are actively involved in researching this? Only certain p[polymorphisms are fatal for infants. There are plenty of us living with partial PNP deficiency. https://pubmed.ncbi.nlm.nih.gov/32695102/ https://pubmed.ncbi.nlm.nih.gov/32695102/ Conclusions: Patients with partial PNP deficiency can present in the third decade of life with mild-moderate immune abnormalities and typical development. Near-normal immunity might be achieved with relatively low PNP activity. > Is it possible that you were a carrier, but homogenous for the variant? There are many genetic alterations which do not manifest as disease unless you inherit a broken copy from both parents. I am homozygous for four variants known to effect T Cells. There is not only one polymorphism that can reduce enzyme activity, rs1049562 rs1049564 - https://www.researchgate.net/figure/Purine-nucleoside-phosphorylase-PNP-rs1049564-variant-enzyme-activity-and-mRNA_fig2_319408659 https://www.researchgate.net/figure/Purine-nucleoside-phosph... rs1713421 rs1760931
  - PragmaticPulp 4y ago
    If you truly suspect this, it's worth exploring something other than 23andMe. 23andMe is useful, but not known for accuracy. Even their datasets have known to include mislabeled SNPs in past years. > Only certain p[polymorphisms are fatal for infants. There are plenty of us living with partial PNP deficiency. > https://pubmed.ncbi.nlm.nih.gov/32695102/ https://pubmed.ncbi.nlm.nih.gov/32695102/ The finding in this paper is that partial PNP deficiency produced normal development in 2 out of 3 siblings and near-normal immune activity in the 3rd, despite having only 8-11% of the normal PNP activity. The takeaway is that partial PNP deficiency might, in some cases, present with only mild-moderate immune abnormalities or normal functioning.
    - FollowingTheDao 4y ago
      I had my genetics one by 23 and me twice once with the v4 chip, and again with v5 chip. I highly doubt that it would come up the same in both of those runs if there was any type of error. I really don’t understand why it went down plays 23 and me so much. Near normal immune function in the third person is not normal immune function. I am one of the people that are affected. Please don’t tell me my history and please don’t assume you know everything about what I’ve suffered through. I’m so tired of this attitude. When there’s no evidence for something people always seem to want to make it into nothing. When, in fact, if they actually studied it, they would find the evidence. But they don’t and people like me just suffer with immune deficiency and mental illness and nothing gets done.
WFHRenaissance 4y ago
Are you Canadian or something?
- mb7733 4y ago
  They said they are in the US.
astrange 4y ago
23andme is not a medical-grade genetics test. Finding a very rare genetic mutation in it isn't convincing unless you get a specific test for it or do 1000x WGS.
- FollowingTheDao 4y ago
  This is not true whatsoever in any way. It does not have to be “medical grade”. Whatever that means. I mean, are you saying they get their snips wrong constantly.? if so, that’s patently absurd because they went through the testing to assure this doesn’t happen. Or when it does happen, it doesn’t happen with the consistency over different chips.
  - astrange 4y ago
    Yes, they get individual SNPs wrong constantly and for rare results are especially inaccurate. https://journals.lww.com/oncology-times/fulltext/2021/07200/new_study_shows_the_inaccuracy_of_at_home_genetic.7.aspx https://journals.lww.com/oncology-times/fulltext/2021/07200/...
    - FollowingTheDao 4y ago
      Thet get it wrong consistently? Did you even read the study? No you didn’t. Because if you did, you would’ve read this. “Results Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. Conclusions SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.” The SNPs I have are not very rare. And why did the task it wrong twice? Exactly wrong twice, they got all four SNPs exactly wrong twice? If you wanna give me the money to get a full genome test please send it to me and I’ll prove you were wrong. Because I’m currently homeless and on disability trying to fucking fix whatever problem I have no one fucking cares about.
atdrummond 4y ago
May I ask where you are located, roughly? YMMV but I was given genetics tests for my leukaemia, polycythemia vera and Crohns. All were routine. I actually had more issues getting a thiopurine metabolites test ordered than I did with any of my genetic tests.
- FollowingTheDao 4y ago
  I am in the US. My issue is that I was diagnosed with a mood disorder before anything else. So now, even though my white blood counts, never get above four, well, not until recently. They dismiss any other problems I have. Because I think it’s all because of my brain. It’s so idiotic I can’t stand it. I can’t have any other illness because I have a mental illness. I’ve been telling doctors about my low white blood cell count for a decade. Not one of them does further testing on it. I don’t know how to convince them or what to say , I think one of the problems is I take such good care of my health and so when they look at me I look fine. But it does not show how I feel inside and it does not show the fatigue I deal with. Yo, I want to say you’re lucky that you have leukemia because that’s easily spotted. but I’m one of those people with this borderline chronic health issue that they don’t wanna waste time on because I’m not actively dying. I’m just suffering my whole life.
  - atdrummond 4y ago
    It actually took years for my Leukaemia to be sorted, funnily enough, due to the impacts my autoimmune disease and medications had on my blood levels. I also was told for years I was faking my stomach pains until my leg nearly fell off due to a MRSA infection, which subsequently turned into a case of pyoderma gangrenosum. I was then finally diagnosed with Crohn’s disease. I will say there are some good doctors out there. My email is always open to HN readers if you want some help or advice here. Best of luck regardless.
tsol 4y ago
When it comes to obscure and unlikely illnesses, many doctors have a hard time entertaining the idea. They're taught when they hear hooves to think horses, not zebras. From stories I've heard it seems like it takes trying until you find a doctor open minded enough, or perhaps there's a doctor/researcher that specializes in this area you can reach out to. Not all doctors are the same, to some it's just a job but I'm certain there are some out there that would be okay with exploring that
- FollowingTheDao 4y ago
  Real conversation I had with a doctor. Me: I am still sick; insomnia, anxiety, skin infections, GI Issues, Chronic Fatigue Doctors: Well the only thing wrong is your low WBC count. Me: Why is my WBC count low? Doctor: That's just normal for some people. Me: If is is normal why do you have a lower range? Doctor: Have you been talking with your psychiatrist and therapist? Me: Will they know more about why my white Blood Cell count is low? Doctor: But we just do not know why you feel so unwell. Me: Are there any more tests you can do? Doctor: Are you looking for something to be wrong with you? Me: What? Doctor: You tests are all normal so I ... Me: My tests are NOT normal, my WBC count is low, consistently, and I have reoccurring mild hyperkalemia. Doctor: What test would you like me to do? Me: ...

jauer 4y ago

Eh. Doing it yourself is a huge pain even when you get useful signal. I wish I could pay someone a few k$ to check results against literature and a list of things I think are weird with my body. ex. I have family history and symptoms of hypothyroidism. I've had 3 doctors test T4&TSH, then shrug and say everything is fine. My dad had a similar experience before landing on a doc who shrugged and said "let's just try the meds anyway and see what happens." I got WGS out of curiosity, annotated the VCF with REVL scores, and sorted by score. The first entry was a low-frequency (121 hits in TopMed) NR1D1 missense variant. I couldn't find any literature on that variant, so I looked at the downstream THRA impact and found papers that talked about disruption to thyroid signaling, and said that T4 & TSH would look normal, so you need to check T3/rT3. I bounce this off my endo and ask if she'll order a T3 & rT3 test. She won't because endo society guidelines says that rT3 tests aren't clinically useful. I order my own tests from a labcorp reseller. My T3 & rT3 results reflect what the papers saw, so I get grey market thyroxine. Screw up the dosing and get a day of racing heart. Fix dosing and hypothyroid symptoms went away. After this I find out that there's a whole community of people with normal T4 & TSH results, hypothyroid symptoms, and wonky T3/rT3. Also that there's some kind of culture clash between normal docs and functional medicine docs about this.</shrug> I shouldn't have to resort to days of messing with bioinformatics tooling, a week of reading papers, and questionable sourcing of meds to test something that any doc should have been able to deduce if they bothered to have some curiosity about how I could have those symptoms if their normal test came back normal :(

phnofive 4y ago
Great job sticking with it - it's not easy and it is lonely, but you did it.
buildbot 4y ago
BTW there is a tool for this, though you seem like you did well on your own - promethease https://www.promethease.com/ https://www.promethease.com/
hallway_monitor 4y ago
Maybe a better doctor could get you the medicine you need. The ideal solution is to make many prescription meds available over the counter since doctors are often useless or actively harmful though their ignorance and hubris.

nibbleshifter 4y ago

> You can do it yourself for under $500 if you really want. I'm interested in learning more about this. I'd fucking love to get my whole genome sequenced and be given the raw data.

chromatin 4y ago
https://nebula.org/whole-genome-sequencing-dna-test/ https://nebula.org/whole-genome-sequencing-dna-test/

strbean 4y ago

Quick plug for https://brcaexchange.org/ https://brcaexchange.org/ It's a database of known BRCA1 and BRCA2 variants with significance scores and links to clinical research. If you get results telling you that you have variants in those genes, look them up here (under the guidance of a genetic counselor, of course).