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Comment by FollowingTheDao | Hacker News Reader

> 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.

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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.

>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/

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-phosph... rs1713421 rs1760931

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/

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.

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.

Seriously talk to someone who does clinical genomics not 23andme. Our institute does various tests and the closest one to 23andme is ngs with avg read depth of 2000 and we still get a bunch of errors in reads and we have huge lists of known artifacts that we only know about because we actually do the clinical correlation

> Seriously talk to someone who does clinical genomics not 23andme.

Really? Just go and talk to someone? I am homeless with a mental illness on top of the immune dysfunction. You think this is something I have not tried over and over for the last ten years?

And again, if it WAS an error, why did it show up TWICE, and no one else I who I have 23andme genetics (15 people!) have more than heterozygous SNPs for these?

Please, explain that to me and I will waste more time having doctors just tell me it is my mental illness and drive myself further to suicide.

I realise this must be hugely frustrating for you. The folks on here are mostly genuine in their attempt to help, even if they seem misguided due to lack of context. If you could find the time and space to be patient with them i'm confident that you may learn something of value.

I admit, this is a rant, but because I am tired and frustrated not only for myself, but for all the people I know and support who are living with chrnoic illnesses. I am not mad at anyone personally.

> The folks on here are mostly genuine in their attempt to help,

Are they? You know what helping people looks like? It has nothing to do with words. All I hear are words all day.

Me: "Can you help me, I need housing?"

Everyone: "Have you looked on Craigslist?"

Me: Can you help me? I am sick and cannot think straight.

Everyone: Have you tried searching for a geneticist?

I am the one who is ill and I am supposed to do all the work? Help is "Hey, I am a geneticist, call this person and ask, or call this person, or call me."

Learn something of value? I am done with learning. I fricking taught myself genetics and neurological biology, I have managed to at least get my self well enough to get off of all my psychiatric medications except for klonopin as needed. I taught myself nutritional genomics and lowered my cholesterol through diet alone, I discovered why EMFs give me insomnia, mania, and palpitations.

So if anyone here is a geneticist and wants to see a real European genetic freak let me know. Here are some hints; NOS1AP, GCH1, PNP, FASD1, FADS2, CPT1A, BTD, SLC18A1, SLC18A2, ERAP1, FUT2 (non-secretor), NCAN, NRXN1, and ...

I was in one genetic study and they found I was heterozygous for this: GALC c.1685T>C (p.Ile562Thr) I have the document from INVITAE!

I demanded to talk to a genetic counselor. They said it was NOTHING! I showed the geneticists this:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994525/ The GALC enzyme activity of him was low, and the GALC gene analysis revealed compound heterozygous pathogenic mutations of c.1901T>C and c.1901delT.

And they STILL would not test my enzyme activity even when I have episodic spastic paraplegia so bad they thought I had MS! They genetic counselor did not even know what the enzyme did!

I mean what more do I have to do?

ADDING: I mean what is the change that I am a FUT2 non-secretor (Galactoside alpha-(1,2)-fucosyltransferase 2) and have this GALC (Galactocerebrosidase) polymorphism? They both have to do with galactosides!

Having any chronic condition, especially one that's not a "normal" condition with a treatment script (like say Diabetes), causes one to discover really fast that most health advice is useless at best, most doctors are maybe only 10% better than that and you will have to do far more work than you ever thought in keeping yourself alive. Most people will be more concerned with the idea that you might be faking something and getting away with it than actually trying to solve the issues at hand. I'm sorry to find another soul going through it, and I have nothing more to offer than condolences and wishes of good luck in finding a doctor that will actually listen and stick around.

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.

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.

Yes, they get individual SNPs wrong constantly and for rare results are especially inaccurate.

https://journals.lww.com/oncology-times/fulltext/2021/07200/...

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.

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

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: ...

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.

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.

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.

Are you Canadian or something?

They said they are in the US.

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