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VUS MDT Meetings Part 2: Good communication
VUS MDT Meetings Part 2 - Good communication
Hi, everyone. I’m Beth Coad. I’m a genetic counsellor here at St. George’s, and I’ll be chairing our VUS MDT today. As always, we work into the ACMG and ACGS guidelines for variant interpretation. In the meeting room today, we’ve got it up on the second screen, the summary table from that. But it was also attached to all of your meeting invites. So for those of you at home, do click that link and have that open as we go through, just as the reminder. On the call we also have our clinical genetics registrar, Dr. Alex Deng, and we have our clinical scientist, Clinda Puvirajasinghe, Clinda have I said that right? Yes, you have. Brilliant.
Thanks, Clinda And we’ve also got trainee genetic counsellor who’s just observing and listening in today. That’s Kate James. And we are also joined by Dr. Walker, who’s a paediatrician who’s got a case to discuss. As you can see from our list, the first case is Grace, who has been found to have a c.56a5 C to G missense variant in the NSD1 gene. I’ll just say the performer now for this variant, and Grace’s paediatrician, Dr. Walker, can tell us a little bit more about Grace and why she’s brought this variant. Hi, everyone. I met Grace a few months ago with her parents in the clinic. And she’s a four-year-old girl with global developmental delay.
When I examined her, I noticed she’s big for her age in terms of both height and head circumference. I decided to request exome sequencing to look for an explanation for her delay. And I understand that this identified a bus in the NSD1 gene. So I brought this to the meeting today to see if the group feel this might explain Grace’s difficulties. Super. And so thanks, Dr. Walker. I guess a good place to start would be whether you thought there were any other distinctive facial features, other than the large head? Do you have a photo that you could share? Because we associate with NSD1 gene with the genetic syndrome called Sotos syndrome, where you see quite a distinctive facial appearance.
Yeah, I do actually have a photo. I sent it around before. I think you probably got it? Yes. Yeah, we do. Thank you, Dr. Walker. Kate, as you helped us prepare for this meeting, would you mind just screen sharing the photo that Dr. Walker sent of Grace?
Great. Thank you. OK, that’s really helpful. That shows Grace has quite a few features of Sotos syndrome. She’s quite a prominent chin. Quite a long head, known as dolichocephaly. She also has these down slanting palpable fissures, which we can see from the downward point of the outside of her eyes. Could you remind me what are her growth parameters? Well, her head circumference is greater than 2.3 standard deviations above what we’d expect for her age. And her height and her weight are also plus 2 standard deviations. That’s really useful. So in fact, this constellation of clinical features is very characteristic of Sotos, by which I mean she has the facial gestalt. She has intellectual disability.
And she has a childhood onset overgrowth with her head and her height 2 standard deviations above the mean. I think that according to ACGS criteria, this highly specific phenotype lets us apply PP4 at a moderate level. In fact, I think they use the Sotos syndrome as an example in their 2020 update document for this. OK. So that’s brilliant. We’ve got a good picture of the phenotype. So moving on, onto the family history. Dr. Walker, was there any reported family history in the family? Anything like learning difficulties, or similar facial features to Grace at all? No, none at all. Both parents were well. Neither reported any learning difficulties. And nothing in the wider family. OK.
So thinking about what we know on inheritance, as we’ve done an exome on Grace and both of her parents, we know that this is de novo. So meaning it was not found in either of the parents, and is something that occurred in Grace for the first time. The ACMG evidence category for this kind of inheritance data is PS2. So given that we know that this variant is de novo, we have confirmed both paternity and maternity, and it sounds like we’re happy that Grace’s phenotype fits really, really well, would we all be happy to use this evidence as strong strength, given that previous discussion about the phenotype? I’m sorry. Can I just check, what’s the significance of the confirmed parentage?
So without this confirmation, we are left with the uncertainty that a variant may not be truly de novo. And instead, it could have been inherited from an unknown biological parent, for example, non paternity. And in order to use this information as strong evidence, the ACMG and ACGS guidance states the variant should also fully account for the patient’s phenotype. And as Alex mentioned, it sounds like we are confident that Sotos syndrome is associated with SMD1 one, and it fits for Grace, and that the phenotype is very specific. Yep. Certainly. Using PS2 for strong is appropriate here. Good. Great. OK. Brilliant. Thanks, everyone. So this is some evidence in support of pathogenicity.
So at the lab, are there any other thoughts on the actual variant itself? Yes, so we also looked at gnomAD healthy population database, and this did include any normal individuals carrying this variant. So we can use PM2 at moderate level. Also having a look at the gene in a bit more detail looks like this gene does not tolerate missense variation because it has a significant missense constraint score. Given this, we can also use PP2 at supporting. Is everyone in agreement with these classifications so far? Yeah. Good. In addition, multiple intellectuals were in agreement that this amino acid substitution was likely to be damaging. So we can also use PP3 at supporting here.
It gets a little bit more complicated with PM5. PM5 looks at whether another amino acid change has been reported at the same position. On Kalimba, there have been a couple other missense variants reported at the same amino acid position, namely a cystine to a phenylalanine, and also a cystine to a tyrosine. And just to remind you that our change is a cystine to a tryptophan. And the lab have analysed the other variants independently, and we would not class these variants as likely pathogenic or pathogenic according to the ACMG or the ACGS criteria. So unfortunately, that means we cannot use the PM5 line of evidence. How do people feel about this? Fine. Brilliant. That’s great.
Thank you, Clinda So I’m aware we’ve gone through quite a few different categories there. So would you mind just summarising all the evidence that we do have for this variant? No, of course. So it sounds like we are in agreement that we don’t have any evidence to support this variant as being benign. And in terms of evidence to support pathogenicity, we have, firstly, the fact that it’s absent from population database. So that’s PM2, a moderate strength. We also have in silico tools suggesting it has a deleterious effect. So it’s PP3 at supporting strength. We have missense variant in a gene with low rates of benign missense variation. That’s PP2 at supporting strength.
We have the fact that this variant is de novo, with paternity and maternity confirmed. And the phenotype fits, and it’s very specific for Sotos. So we can use PS2 at strong. And because of this, we are also able to use PP4 immoderate, which is evident with this gene and phenotype are specific. In total, that gives us two pieces of supporting evidence, two pieces of moderate strength evidence, and one strong evidence. And in combination, this means we can classify this variant as pathogenic. That’s great. Are we all happy with that classification? Yeah. Yeah. Sounds good. Brilliant. That’s really good news. It seems like we’ve found the explanation, given that the phenotype fits. So Dr.
Walker, did you have any questions about everything we’ve been through at all? And what would you like us to add to the clinical action column for the log of this meeting? Thanks, everyone. That all makes sense, actually. As for the actions, once I’ve received the lab report, I’ll be feeding back to the family that we’re confident that this variant is a good explanation for Grace’s developmental delay. And we’ll manage her as a Sotos syndrome patient. So I’m sure the family will be really pleased to have an answer. Brilliant. That’s great. Thank you, Dr. Walker, for coming along today. So now we’re going to move on to our next variant on the list.
In this video, our clinicians and scientists have another go at discussing Grace’s NSD1 c.5685C>G p.(Cys1895Trp) variant.
Here we see a better outcome to the discussion, with a proforma summarising what the outcome would have been available here.
As well as seeing a proforma, the participants in this meeting are told to review the ACMG guidelines and are also shown an image of Grace.
As Grace was a fabricated patient for this course we do not have a photo of her to share, instead a placeholder of a different child with Sotos syndrome has bene used to help you familiarise yourself with the characteristic features.
In practice, it is very helpful to share photos of patients to consider how well the phenotype fits.
Our communications expert, Dr Katherine Joekes, has given us her observations of how the communication was improved in this MDT.
Take some time to identify what was different in this second MDT.Beth, the Genetic Counsellor, took on the role of Chair, and ensured that everyone was introduced, that the case was introduced, and everyone was able to contribute.The variant classification was explained, which meant that Dr Walker, the paediatrician in this MDT, was aware of the process. She was explicitly invited to query any jargon she did not understand.As the MDT was more structured, it allowed more detail to emerge from the paediatrician, the scientist, and the clinical geneticist. This enabled a more comprehensive sharing of information.Jargon was explained, where necessary. A conclusion was drawn, and the paediatrician was able to leave the MDT with a clear message to feedback to the parents.A brief note about time. You will have noticed that the second meeting took longer. It is important to accept that more effective meetings require more time on the day. However, in the long run they ensure better outcomes for the patient, and less time is wasted down the line for the family and for (other) healthcare professionals.
To summarise the good practice:
- An effective Chair manages the meeting.
- Jargon is reduced and/or explained
- Dr Walker is invited to summarise what she will relay to the family. This allows all members of the MDT to check that the information is understood and will be relayed accurately.
- Reference is made to up-to-date guidance
- Adequate time is taken for a comprehensive discussion
For those taking part in the external course evaluation please follow this link to provide feedback for the step.
This article is from the online course:
Interpreting Genomic Variation: Fundamental Principles
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Interpreting Genomic Variation: Fundamental Principles
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