6 ms·

> nobody has said, "We should consider looking at your DNA to see what's up here. I'm really interested and want to figure this out with you." The vast majorit

> nobody has said, "We should consider looking at your DNA to see what's up here. I'm really interested and want to figure this out with you." The vast majority of doctors don't have the expertise or resources needed to do that. 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. And even if they did manage to sequencing done and a novel mutation popped up, there isn't anything to do with that treatment-wise. The next step would be going back to the lab, synthesizing mutant RNA and/or peptide sequences and studying their properties. And it would likely take years for that to translate into knowledge that is clinically useful. If you want that kind of care, you need a large, academic hospital that has an ultraspecialist with an active and well funded research program in the relevant area. They can cover the costs of nonstandard tests out of their research funds. And if unusual findings pop up, they have the equipment/resources to follow that up with further studies.

PragmaticPulp 4y ago
> 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
- 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).
giantg2 4y ago
Doesn't NIH cover the genome sequencing if its an unexplained illness? I think it's more a matter of the doctors not knowing how to refer someone for that.
- Calavar 4y ago
  > Doesn't NIH cover the genome sequencing if its an unexplained illness? No, they don't. And it wouldn't make sense for them to do that either. There isn't much value to that clinically (sequencing is highly unlikely to reveal a new treatment pathway - there's only a handful of specific mutations for which we have specific treatments - cystic fibrosis, sickle cell, PKU, hemophilia, etc.) or from a research perspective. (Research answers a hypothesis driven question; usually that means you have a particular clinical syndrome and a theory about how it arises. Randomly turning over stones in search of something with out any clear idea of what you're looking for is essentially distributed p hacking and unlikely to lead to anything except for wild goose chases after statistical noise.) Are you referring to this [1] program? If so, they have a very specific list of diseases that they are sequencing for. It's not open season for any unexplained symptoms. (And how you would rigorously define unexplained if you don't have a particular syndrome in mind is a whole other can of worms) [1] https://www.nih.gov/news-events/news-releases/nih-genome-sequencing-program-targets-genomic-bases-common-rare-disease https://www.nih.gov/news-events/news-releases/nih-genome-seq...
  - giantg2 4y ago
    It's not like anyone can just apply. It looks like sequencing is open to any NIAD participant, people who might fit specific diseases, or based on collaboration with other researchers on a case by case basis. It doesn't seem like they're that picky when they've sequenced over 100k people already. https://www.niaid.nih.gov/research/centralized-sequencing-program https://www.niaid.nih.gov/research/centralized-sequencing-pr...
  - CrazyStat 4y ago
    More likely the Undiagnosed Diseases Network [1], though my understanding is it's fairly difficult to actually get taken on as a patient. [1] https://undiagnosed.hms.harvard.edu/ https://undiagnosed.hms.harvard.edu/

PragmaticPulp 4y ago

> 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
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).

giantg2 4y ago

Doesn't NIH cover the genome sequencing if its an unexplained illness? I think it's more a matter of the doctors not knowing how to refer someone for that.

Calavar 4y ago
> Doesn't NIH cover the genome sequencing if its an unexplained illness? No, they don't. And it wouldn't make sense for them to do that either. There isn't much value to that clinically (sequencing is highly unlikely to reveal a new treatment pathway - there's only a handful of specific mutations for which we have specific treatments - cystic fibrosis, sickle cell, PKU, hemophilia, etc.) or from a research perspective. (Research answers a hypothesis driven question; usually that means you have a particular clinical syndrome and a theory about how it arises. Randomly turning over stones in search of something with out any clear idea of what you're looking for is essentially distributed p hacking and unlikely to lead to anything except for wild goose chases after statistical noise.) Are you referring to this [1] program? If so, they have a very specific list of diseases that they are sequencing for. It's not open season for any unexplained symptoms. (And how you would rigorously define unexplained if you don't have a particular syndrome in mind is a whole other can of worms) [1] https://www.nih.gov/news-events/news-releases/nih-genome-sequencing-program-targets-genomic-bases-common-rare-disease https://www.nih.gov/news-events/news-releases/nih-genome-seq...
- giantg2 4y ago
  It's not like anyone can just apply. It looks like sequencing is open to any NIAD participant, people who might fit specific diseases, or based on collaboration with other researchers on a case by case basis. It doesn't seem like they're that picky when they've sequenced over 100k people already. https://www.niaid.nih.gov/research/centralized-sequencing-program https://www.niaid.nih.gov/research/centralized-sequencing-pr...
- CrazyStat 4y ago
  More likely the Undiagnosed Diseases Network [1], though my understanding is it's fairly difficult to actually get taken on as a patient. [1] https://undiagnosed.hms.harvard.edu/ https://undiagnosed.hms.harvard.edu/