lunarainbows
Senior Member (Voting Rights)
Whole genome sequencing - NHS
(I had a request to share some of my information about whole genome sequencing on a public thread so more people could find it
)
Ok so because I’ve been reading a lot about whole genome sequencing (on the NHS) recently, and I’ve gone through it all myself, I thought I’d do a post about everything I’ve learned? Rather than letting it all just sit in my head! It’s very different to what I thought whole sequencing is and I think others would agree.
So the first thing is on the NHS atm, whole genome sequencing clinically seems to be mostly done with panels. they sequence your genes but then run it through the panels - ie only those genes are looked at. There are panels for various conditions, some childhood diseases, and there is a panel for metabolic conditions (called “likely inborn error of metabolism” - that’s the R98). Each area in the country has different tests that they’ve agreed can be requested, and one example of all the panels available is this: NHS panels.
And there is an eligibility criteria for a patient to have WGS. Which is very long and I have not read it. But here for your information.
The blood is sent off to the lab (after a discussion with the patient). At the same time, blood is taken from both biological parents (which is what the NHS ideally prefers), or from one biological parent. “For the majority of clinical indications currently being tested, it is highly recommended that a trio is referred for testing (proband and biological parents), however it is acceptable to refer a duo (proband and one biological parent) or singleton where one or more parents are not available. It is recognised that for some patients, with an adult-onset disorder, parental samples will not be available and singleton testing will be required.” More info
The parent(s) will be classed as either affected or unaffected. This is decided by the doctor who is ordering the WGS - if they get this wrong, then the results won’t be right. If they class the parent as unaffected (and choose something called “complete penetrance”), then any genes that the patient and parent shares, will be filtered out. However if a parent is affected, those genes will be looked at because they could be causing illness. If the doctor isn’t sure about it, or thinks perhaps the parent could just be mildly affected, they can choose “incomplete penetrance” which means they still take the parents blood, but just won’t filter out anything that is shared between parent and the patient, just incase.
For me - the doctor said my mum is unaffected (despite my mum sharing some of the same symptoms as me, just milder), and then also chose complete penetrance (as he said before that shared genes between me and my mum would be filtered out). As a consequence, anything my mum shares with me was most likely filtered out and whatever was left, was then used.
Of the genes that were left - these were then run through the R98 (metabolic myopathy) panel, and it’s only the genes in the panel that were analysed. Other genes that aren’t in the panel, wouldn’t have been looked at.
In addition to this, when the doctor sends off for WGS, they have to give clinical information - keywords. These are called HPO - human phenotype ontology. These are supposed to describe the patient’s symptoms, and the people running the whole genome sequencing will only look at the variants which match these terms. If a variant is found but it doesn’t match these terms, then they will just discard the variant too: “ A note on HPO terms: Human Phenotype Ontology (HPO) terms are utilised to provide standardised terms for the clinical features of patients. The website which lists all of the available terms can be found here https://hpo.jax.org/app/. It is vitally important that the correct HPO terms are entered for patients onto the Test Order Form, as this can directly impact the analysis of the patient data. For example, variants identified through WGS that do not appear to fit with the clinical features of the patient, as provided through the HPO terms, may not be considered likely relevant to the patient phenotype.”
And relating this back to me.. looking at the report I’ve now got, they have used at least one wrong HPO term - a symptom I don’t even have! They also didn’t use HPO terms of the majority of symptoms I actually do have - symptoms I had from when I was a child.
I believe it was different back during the 100,000 genomes project when they did really look into the genome deeply, but now clinically it looks like it’s not usually like that. Yes they do technically sequence your whole genome.. but then they get rid of so much of it. They filter out so many genes based on your parents and based on the subjective decisions of the doctor. Then they run it through just one or two panels of genes based on what the doctor thinks your presentation is. Then they filter out even more based on what the doctor decided were your HPO terms. There’s so much that hinges on what the doctor thinks or wrote about you.
There’s a lot that isn’t analysed or looked at that could hold clues. Just as one example, my muscle biopsy came back with evidence of a specific neuromuscular condition. But none of the genes related to that condition would have even been looked at as that wasn’t in the panel. I also may even right now have one of the genes in the metabolic myopathy panel, but I wouldn’t know, because they’ve already filtered out anything that me and my mum share before even checking the panel. Despite my mum also having symptoms of the condition.
I don’t know the reason why they do it all this way.. but the only reason I can think is to make it “easier” for geneticists to find things.. and cynically, it’s probably also a lot cheaper and less time for the geneticists. But while they’re doing that, so much can get lost and patients may even miss out on finding a genetic variant for their symptoms.
(I had a request to share some of my information about whole genome sequencing on a public thread so more people could find it
)Ok so because I’ve been reading a lot about whole genome sequencing (on the NHS) recently, and I’ve gone through it all myself, I thought I’d do a post about everything I’ve learned? Rather than letting it all just sit in my head! It’s very different to what I thought whole sequencing is and I think others would agree.
So the first thing is on the NHS atm, whole genome sequencing clinically seems to be mostly done with panels. they sequence your genes but then run it through the panels - ie only those genes are looked at. There are panels for various conditions, some childhood diseases, and there is a panel for metabolic conditions (called “likely inborn error of metabolism” - that’s the R98). Each area in the country has different tests that they’ve agreed can be requested, and one example of all the panels available is this: NHS panels.
And there is an eligibility criteria for a patient to have WGS. Which is very long and I have not read it. But here for your information.
The blood is sent off to the lab (after a discussion with the patient). At the same time, blood is taken from both biological parents (which is what the NHS ideally prefers), or from one biological parent. “For the majority of clinical indications currently being tested, it is highly recommended that a trio is referred for testing (proband and biological parents), however it is acceptable to refer a duo (proband and one biological parent) or singleton where one or more parents are not available. It is recognised that for some patients, with an adult-onset disorder, parental samples will not be available and singleton testing will be required.” More info
The parent(s) will be classed as either affected or unaffected. This is decided by the doctor who is ordering the WGS - if they get this wrong, then the results won’t be right. If they class the parent as unaffected (and choose something called “complete penetrance”), then any genes that the patient and parent shares, will be filtered out. However if a parent is affected, those genes will be looked at because they could be causing illness. If the doctor isn’t sure about it, or thinks perhaps the parent could just be mildly affected, they can choose “incomplete penetrance” which means they still take the parents blood, but just won’t filter out anything that is shared between parent and the patient, just incase.
For me - the doctor said my mum is unaffected (despite my mum sharing some of the same symptoms as me, just milder), and then also chose complete penetrance (as he said before that shared genes between me and my mum would be filtered out). As a consequence, anything my mum shares with me was most likely filtered out and whatever was left, was then used.
Of the genes that were left - these were then run through the R98 (metabolic myopathy) panel, and it’s only the genes in the panel that were analysed. Other genes that aren’t in the panel, wouldn’t have been looked at.
In addition to this, when the doctor sends off for WGS, they have to give clinical information - keywords. These are called HPO - human phenotype ontology. These are supposed to describe the patient’s symptoms, and the people running the whole genome sequencing will only look at the variants which match these terms. If a variant is found but it doesn’t match these terms, then they will just discard the variant too: “ A note on HPO terms: Human Phenotype Ontology (HPO) terms are utilised to provide standardised terms for the clinical features of patients. The website which lists all of the available terms can be found here https://hpo.jax.org/app/. It is vitally important that the correct HPO terms are entered for patients onto the Test Order Form, as this can directly impact the analysis of the patient data. For example, variants identified through WGS that do not appear to fit with the clinical features of the patient, as provided through the HPO terms, may not be considered likely relevant to the patient phenotype.”
And relating this back to me.. looking at the report I’ve now got, they have used at least one wrong HPO term - a symptom I don’t even have! They also didn’t use HPO terms of the majority of symptoms I actually do have - symptoms I had from when I was a child.
I believe it was different back during the 100,000 genomes project when they did really look into the genome deeply, but now clinically it looks like it’s not usually like that. Yes they do technically sequence your whole genome.. but then they get rid of so much of it. They filter out so many genes based on your parents and based on the subjective decisions of the doctor. Then they run it through just one or two panels of genes based on what the doctor thinks your presentation is. Then they filter out even more based on what the doctor decided were your HPO terms. There’s so much that hinges on what the doctor thinks or wrote about you.
There’s a lot that isn’t analysed or looked at that could hold clues. Just as one example, my muscle biopsy came back with evidence of a specific neuromuscular condition. But none of the genes related to that condition would have even been looked at as that wasn’t in the panel. I also may even right now have one of the genes in the metabolic myopathy panel, but I wouldn’t know, because they’ve already filtered out anything that me and my mum share before even checking the panel. Despite my mum also having symptoms of the condition.
I don’t know the reason why they do it all this way.. but the only reason I can think is to make it “easier” for geneticists to find things.. and cynically, it’s probably also a lot cheaper and less time for the geneticists. But while they’re doing that, so much can get lost and patients may even miss out on finding a genetic variant for their symptoms.
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