Non-coding Region variant Flashcards
What was the recent variant found in in the non-coding region?
A recent research findings which have found a genetic change in the non-coding RNU4-2 gene, to be linked to neurodevelopmental conditions.
It was made possible by research using data from the National Genomic Research Library
Podcast and the case discussion
With no diagnosis, they had no prognosis.
They couldn’t do family planning.
The child had to undergo myriads of genetic tests.
But I think one of the things that’s really extraordinary about this one is that actually it turns out to be much more common than we might have expected, for one of these new conditions that we haven’t found before. But I think it’s about one in 200 of those undiagnosed children with neurodevelopmental conditions, have this diagnosis so that’s not a small number. That’s not a rare finding at all actually, that’s much more common than we could ever have anticipated.
The Genomics England dataset we have sequencing information on the entire genome, not just on these protein coding genes and that means we can also look at variants in other genes. So, those that make molecules other than proteins. And RNU4-2 for example, makes an RNA molecule.
it highlights the power of the National Health Service in that we were able to create such a resource. It’s really quite astounding that we’ve found such a common cause of a rare genetic condition, and it wouldn’t have happened in the same timescale or in this way without that resource.
But all that came from that power of sharing data and being able to have that all in one place and making it accessible to very clever people who could do this work and find these answers. It’s so important for families like Lindsay’s, and all the families in England and around the world that have got these answers. So, I guess it’s a big plug for the value of data sharing and having a secure place where people feel that it’s trusted and safe, that enables these diagnoses to be made.
So, you asked me earlier about why it had taken so long to find this particular cause of neurodevelopmental condition, and I gave you a relatively simple answer. The reality is one of the other reasons is that almost eight out of ten children and adults who have RNU4-2 related neurodevelopmental condition have exactly the same single letter spelling change in that gene. So, actually that in itself means that when researchers are looking at that information, they might think that it’s actually a mistake. Because we know that when we sequence genetic information, we can see mistakes in that sequencing information that are just because the machine has, and the way that we process that data, it’s not perfect. So, sometimes we find these little mistakes and they’re not actually the cause of a person’s problems, they’re just what we call an artefact or an issue with the way that that happens.
But that in itself is quite helpful when we think about how we might identify more people who have this going forwards. Because unlike in Lars’ case where we didn’t know what the cause was and so we were still searching, and we didn’t know where to look in the billions of letters that make up the genetic code to find that answer, we now know that this is really very common. It’s unbelievably common. I think we didn’t think we would be finding a cause of a rare genetic condition that was this commonly occurring at this stage. But the fact that it’s just a single, it’s commonly this one single change in the gene means that we can set up pretty cheap diagnostic testing. Which means that if you were somewhere where you wouldn’t necessarily have access to whole genome sequencing, or a more comprehensive testing in that way, we could still be able to pick up this condition. And it’s common enough that even if you didn’t necessarily recognise that a person had it, you could still have this as part of your diagnostic tool kit for patients who have a neurodevelopmental condition. It’s common enough that just doing a very simple test that could be done in any diagnostic lab anywhere in the world, you would be able to identify the majority of people who have this.
It offers genetic diagnosis not just for a handful of families but potentially for many hundreds of families, who we all know have been searching often for many, many years for a genetic diagnosis. But actually, there are other gains from understanding how this gene causes neurodevelopmental disorder. We know that there’s GRNU4-2 in codes, not a protein actually, but a small nuclear RNA which is unusual for rare, inherited disorders. It’s a component of a very complicated molecule called the spliceosome which in turn regulates how thousands of other genes are regulated, how they’re made into proteins. So, fundamentally this discovery tells us a lot about the biology of how the spliceosome works. We already know that some other components of the spliceosome can go wrong, and result in diseases like neurodevelopmental disorders. This gives us an extra insight and actually opens the door to, I hope, a whole load of more discoveries of genetic diagnosis possible from other components of this complicated molecule.
Podcast and the case discussion
With no diagnosis, they had no prognosis.
They couldn’t do family planning.
The child had to undergo myriads of genetic tests.
But I think one of the things that’s really extraordinary about this one is that actually it turns out to be much more common than we might have expected, for one of these new conditions that we haven’t found before. But I think it’s about one in 200 of those undiagnosed children with neurodevelopmental conditions, have this diagnosis so that’s not a small number. That’s not a rare finding at all actually, that’s much more common than we could ever have anticipated.
The Genomics England dataset we have sequencing information on the entire genome, not just on these protein coding genes and that means we can also look at variants in other genes. So, those that make molecules other than proteins. And RNU4-2 for example, makes an RNA molecule.
it highlights the power of the National Health Service in that we were able to create such a resource. It’s really quite astounding that we’ve found such a common cause of a rare genetic condition, and it wouldn’t have happened in the same timescale or in this way without that resource.
But all that came from that power of sharing data and being able to have that all in one place and making it accessible to very clever people who could do this work and find these answers. It’s so important for families like Lindsay’s, and all the families in England and around the world that have got these answers. So, I guess it’s a big plug for the value of data sharing and having a secure place where people feel that it’s trusted and safe, that enables these diagnoses to be made.
So, you asked me earlier about why it had taken so long to find this particular cause of neurodevelopmental condition, and I gave you a relatively simple answer. The reality is one of the other reasons is that almost eight out of ten children and adults who have RNU4-2 related neurodevelopmental condition have exactly the same single letter spelling change in that gene. So, actually that in itself means that when researchers are looking at that information, they might think that it’s actually a mistake. Because we know that when we sequence genetic information, we can see mistakes in that sequencing information that are just because the machine has, and the way that we process that data, it’s not perfect. So, sometimes we find these little mistakes and they’re not actually the cause of a person’s problems, they’re just what we call an artefact or an issue with the way that that happens.
But that in itself is quite helpful when we think about how we might identify more people who have this going forwards. Because unlike in Lars’ case where we didn’t know what the cause was and so we were still searching, and we didn’t know where to look in the billions of letters that make up the genetic code to find that answer, we now know that this is really very common. It’s unbelievably common. I think we didn’t think we would be finding a cause of a rare genetic condition that was this commonly occurring at this stage. But the fact that it’s just a single, it’s commonly this one single change in the gene means that we can set up pretty cheap diagnostic testing. Which means that if you were somewhere where you wouldn’t necessarily have access to whole genome sequencing, or a more comprehensive testing in that way, we could still be able to pick up this condition. And it’s common enough that even if you didn’t necessarily recognise that a person had it, you could still have this as part of your diagnostic tool kit for patients who have a neurodevelopmental condition. It’s common enough that just doing a very simple test that could be done in any diagnostic lab anywhere in the world, you would be able to identify the majority of people who have this.
It offers genetic diagnosis not just for a handful of families but potentially for many hundreds of families, who we all know have been searching often for many, many years for a genetic diagnosis. But actually, there are other gains from understanding how this gene causes neurodevelopmental disorder. We know that there’s GRNU4-2 in codes, not a protein actually, but a small nuclear RNA which is unusual for rare, inherited disorders. It’s a component of a very complicated molecule called the spliceosome which in turn regulates how thousands of other genes are regulated, how they’re made into proteins. So, fundamentally this discovery tells us a lot about the biology of how the spliceosome works. We already know that some other components of the spliceosome can go wrong, and result in diseases like neurodevelopmental disorders. This gives us an extra insight and actually opens the door to, I hope, a whole load of more discoveries of genetic diagnosis possible from other components of this complicated molecule.
