Dravet syndrome

[mhughes5]

Mondo term (ID and Label)

MONDO: 0011794 Dravet syndrome

Suggested revision and reasons This term should be moved out from early infantile epileptic encephalopathy (MONDO:0016021) because the age of onset is after 6 months. It should instead be placed under developmental and epileptic encephalopathy (MONDO:0100062). This is requested by ClinGen's Epilepsy Gene Curation Expert Panel. Please let me, @Kellytoner or @ErinRiggs know if you have any questions! Thank you!

[cmungall]

Currently we declare this to be equivalent to https://omim.org/entry/607208 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 6; EIEE6 DRAVET SYNDROME

So I think we need to do a broader examination here. Is Dravet and EIEE6 truly the same thing, and EIEE6 is a misnomer? If so we should annotate out synonyms appropriately. Or are Dravet and EIEE6 actually different? If so we should split this class.

Sorry for the delay, but the goal is to have everything be as clear and consistent as possible!

[ErinRiggs]

Hi Chris. Dravet syndrome is a clinical diagnosis - most individuals do indeed have variants in SCN1A, but not all, which is one of the reasons why we do not want it exclusively tied to SCN1A, as is implied by using the term EIEE6. Additionally, our experts note that onset of Dravet syndrome is not "early-onset," so the EIEE term is misleading.

Totally understand the desire to have everything clear and consistent! Please don't hesitate to reach out if you have further questions.

[nicolevasilevsky]

Ok - my understanding is we should split these classes and make a new class for 'EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 6; EIEE6', which would be a child of MONDO_0016021 'early infantile epileptic encephalopathy'

text def: Any early infantile epileptic encephalopathy in which the cause of the disease is a mutation in the SCN1A gene.

@cmungall could you please confirm? Also, should we let OMIM know?

[cmungall]

Yes - split the classes. Add notes that these are distinct and point back to this ticket.

How should we relate these two? We have the shares_featurs_of relation, which would be correct, but is weak - is there a stronger connection to be made? Shared superclass?

[nicolevasilevsky]

I added disease_shares_feature_of relation term, let me know if you prefer something different

[kellytoner]

Hi - just checking in on this issue. We are hoping to do another curation with dravet and were hoping this change could be made before then. Thanks!

[nicolevasilevsky]

@cmungall I think the PR is ready to merge, I addressed your requested changes.

[PabloBotas]

Hi everyone! I am a bit confused here. I was reviewing Dravet in MONDO and came across this. Let's see if I write it properly:

1. Dravet (MONDO:0011794) has an EXACT synonym in "epileptic encephalopathy, early infantile, type 6" according to MONDORULE:1.
2. EIEE6 (MONDO:0100079) is_a EIEE caused by SCN1A
3. EIEE6 (MONDO:0100079) is_a EIEE that shares features with Dravet
4. EIEE4 (MONDO:0012812) is_a Dravet caused by STXBP1
5. EIEE19 (MONDO:0014328) is_a Dravet caused by GABRA1

My understanding here is that EIEE6 and Dravet are synonyms, yet not linked by "is_a"... and that EIEE4 and EIEE19 "is_a" Dravet. But that means that mutations in STXBP1 and GABRA1 somehow hierarchically linked to mutations in SCN1A.

Am I understanding this correctly? I suspect I might not be understanding the "disease_shares_features_of" relation here. Any explanation for a troubled mind? :)

Best, Pablo

[PabloBotas]

Hi, adding on this issue: Checking the phenotype in MONDO, it provides 56 symptoms for Dravet (https://monarchinitiative.org/disease/MONDO:0011794#phenotype). None of these symptoms come directly from EIEE6 as far as I know, unless those annotated to Dravet actually are inherited through the "disease_shares_features_with" annotation.

In any case, discussing with some people from the European Dravet Federation, they say that EIEE4 should not be included under Dravet. From what I gathered, Dravet as a concept/term should be identified with EIEE6. OMIM provides a short-list of symptoms that they say is much better defined compared to the one MONDO provides.

Essentially the thought process in MONDO is reflected in the following. If you were to provide a symptom checklist for somebody saying he/she has Dravet with no further information, then you should provide a list encompassing EIEE6, EIEE4 and EIEE19 (plus direct phenotype annotations to the Dravet term if available. I think West Syndrome is such a case). I like this approach, and it should work... provided that the list of gene-level diseases under Dravet is correct (which, according to some people in the European Dravet Federation, is not).

[nicolevasilevsky]

Hi @PabloBotas - Thanks for bringing up this issue. Above, it looks like the decision was made to split Dravet syndrome from EIEE6, so 'epileptic encephalopathy, early infantile, type 6' should be made a related synonym for 'Dravet syndrome'.

I agree that we should exclude the superclass assertions for 'epileptic encephalopathy, early infantile, 19' and 'epileptic encephalopathy, early infantile, 4'. I will take care of this.

[PabloBotas]

Hi Nicole! Thanks! So this means that now EIEE4 & 19 are not Dravet and that Dravet is a synonym of EIEE6. Is that correct? Is it left as "related synonym"?

This opens a question: do you have a way of checking that there are no hierarchical relation between gene-level diseases in MONDO?

[cmungall]

This check is a high priority. Nicole let's make sure we get this done

On Thu, May 14, 2020, 23:49 Pablo Botas notifications@github.com wrote:

Hi Nicole! Thanks! So this means that now EIEE4 & 19 are not Dravet and that Dravet is a synonym of EIEE6. Is that correct? Is it left as "related synonym"?

This opens a question: do you have a way of checking that there are no hierarchical relation between gene-level diseases in MONDO?

— You are receiving this because you were mentioned. Reply to this email directly, view it on GitHub https://github.com/monarch-initiative/mondo/issues/745#issuecomment-629062521, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAAMMOJ6IJLJOCOBZY4TPOLRRTQYXANCNFSM4H3AAIWA .

[PabloBotas]

Thank you @nicolevasilevsky and @cmungall. Let me know if there is anything I can do to help!! It can get tricky considering relations such as the one you propose between Dravet & EIEE6

[nicolevasilevsky]

So this means that now EIEE4 & 19 are not Dravet

correct

Dravet is a synonym of EIEE6. Is that correct? Is it left as "related synonym"?

No, Dravet is not a synonym of EIEE6, but EIEE6 is left as a related synonym for Dravet syndrome.

[nicolevasilevsky]

do you have a way of checking that there are no hierarchical relation between gene-level diseases in MONDO?

@cmungall how do we check for this?

[cmungall]

can you make a separate ticket for the QC check and assign me/Shahim, thanks.

On Mon, May 18, 2020 at 10:09 PM Nicole Vasilevsky notifications@github.com wrote:

Assigned #745 https://github.com/monarch-initiative/mondo/issues/745 to @cmungall https://github.com/cmungall.

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[julianig72]

Hi there, The average age at seizure onset for Dravet Syndrome is 5.2 months, with a range of 1-18 months, but most often under 12 months (Cetica 2017, Wirrell 2017)

Julian Isla Chief Scientific Officer Dravet Syndrome European Federation

[PabloBotas]

Hi again, Just to clarify Julian's comment. He is commenting in relation to the feedback stating that "our experts note that onset of Dravet syndrome is not "early-onset," so the EIEE term is misleading.".

[nicolevasilevsky]

Hi @julianig72 and @PabloBotas - I'm sorry, I am unclear- is there a specific action item? Thanks!

[cmungall]

@nicolevasilevsky - OMIM:607208 should be equivalent to MONDO:0100079 (EIEE6), not to (MONDO:0011794)

This addresses the comments and the original request I believe

We may want to ask @Orphanet to sync with us, they treat the two as equivalent:

https://www.ebi.ac.uk/ols/ontologies/ordo/terms?iri=http://www.orpha.net/ORDO/Orphanet_33069

[PabloBotas]

Hi @cmungall and @nicolevasilevsky. Julian's point was regarding @ErinRiggs' comment in this thread (https://github.com/monarch-initiative/mondo/issues/745#issuecomment-506424005).

Regarding Chris' comment: I would agree with that. Then there is the issue of: what would MONDO:0011794 be then? Is this consolidating Dravet as a clinical syndrome? In this case, what are the genetic causes it encompasses? SCN1A & GABRA1? This is a complex issue.

[nicolevasilevsky]

OMIM:607208 should be equivalent to MONDO:0100079 (EIEE6), not to (MONDO:0011794)

Thanks Chris, I made this change

[nicolevasilevsky]

Then there is the issue of: what would MONDO:0011794 be then? Is this consolidating Dravet as a clinical syndrome? In this case, what are the genetic causes it encompasses? SCN1A & GABRA1? This is a complex issue.

@PabloBotas good question!

It seems like SCN1A is affected, according to this article: https://pubmed.ncbi.nlm.nih.gov/19673951/

Looks like GABRA1 and STXBP1 as well?: https://pubmed.ncbi.nlm.nih.gov/24623842/

[PabloBotas]

Disclaimer: I am not an expert on Dravet, much less on the field. This is my take on it.

Dravet has been conventionally associated to SCN1A (implying Dravet = EIEE6). However, diseases with similar phenotypes have been attached to the conditions, as you can see with GABRA1 and STXBP1. OMIM's approach is to provide unique names to these, hence the multiple EIEE#. Orphanet doesn't take this approach, hence also holding clinical syndrome definitions.

From private conversations, which I am unable to cite, I gather GABRA1's phenotype is close to SCN1A's, but STXBP1's is (much) more severe. In fact, they have different patient organizations. The bottom line is that these are channelopathies with different causes but similar consequences. I think OMIM's approach here is more accurate and should be used from a scientific perspective. Ultimately we will keep splitting up the diseases in more detailed biological causes (see Becker vs Duchenne distrophies).

From a social/usability perspective, however (and this is a huge however), if you ask a family about the disease they will probably say Dravet, not SCN1A. They will say Dravet, not GABRA1. So the Dravet concept must be retained because it is in use. Nevertheless, I would try to make a conscious effort in slowly shrinking the scope of clinical syndromes. If not for reality (which is often a compelling reason), I would part ways with the clinical syndrome approach :)

Good luck finding an optimal solution for this!! :)

[julianig72]

Hi there, Mutations in GABRA1 lead into much more mild Dravet phenotype named in the past GEFS+. Mutations in STXBP1 produce a much more severe phenotype that Dravet and different clinical features.

There is a general consensus considering Dravet Syndrome is a channelopaty. Just SCN1A is a channel gene.

We are coming from a world where this condition was syndromic but we are moving into a much more precise condition where the border is the gene.

[nicolevasilevsky]

should I add the subclass Of assertion to Dravet syndrome: 'disease has basis in dysfunction of' some SCN1A ?

Seems like this equiv axiom below should be added to epileptic encephalopathy, early infantile, 6 too, as the text def is: Any early infantile epileptic encephalopathy in which the cause of the disease is a mutation in the SCN1A gene.

'early infantile epileptic encephalopathy' and ('disease has basis in dysfunction of' some SCN1A)

[nicolevasilevsky]

thank you @PabloBotas and @julianig72 for all of your input!

[nicolevasilevsky]

action items:

• [x] remove 'early infantile epileptic encephalopathy' as a superclass and other superclasses stating early
• [ ] coordinate with Orphanet (as they say EEE6=Dravet)

[nicolevasilevsky]

@julianig72 and @PabloBotas Do you think Dravet syndrome should be a grouping class (parent class) for EEE6 and 'epileptic encephalopathy, early infantile, 19' ?

[ErinRiggs]

Hello. I will review this exchange with the ClinGen Epilepsy GCEP, the group that requested the original changes to this record, to get their thoughts on this conversation next week.

[nicolevasilevsky]

thanks @ErinRiggs!

[nicolevasilevsky]

@PabloBotas @julianig72 @ErinRiggs

I removed the parents from Dravet: 'early infantile epileptic encephalopathy' 'infancy electroclinical syndrome' (although this is defined as An electroclinical syndrome with onset in infancy occurring between birth and one year of age. - so is this appropriate as a parent for Dravet Syndrome?)

I did not remove 'neonatal/infantile epilepsy syndrome' though, as this was specifically requested by @ihelbig and it is in the ILAE classification of epilepsy:

https://www.epilepsydiagnosis.org/syndrome/dravet-overview.html

This is a complicated subject, it seems! Would you all prefer to have a call to discuss? If yes, could you please send me your contact information so I can coordinate. Thanks!

[PabloBotas]

Hi Nicole, Yes, I think it's best to have a quick call and discuss this. The discussion we are having here should probably be extended to other entities so I think it would be better to settle down a strategy to systematically address them. You can reach me at [removed]. Thanks!

[nicolevasilevsky]

@ErinRiggs and @ihelbig - we are having weekly Mondo calls now on Fridays at 9am PT/12pm ET. Pablo (and perhaps Julian) will join us on Friday to discuss this ticket, if you are available, we'd love for you to join.

[ErinRiggs]

Hello Nicole. I am not available at that time, but I will summarize the brief discussion we had with the ClinGen Epilepsy GCEP today about this topic:

Onset of Dravet syndrome is typically later than the "early infantile" time period, which is why we originally requested that the term be removed from under "early infantile epileptic encephalopathy," and instead be listed as a child of "developmental and epileptic encephalopathy." Though the original ticket was closed, it does not look like this move took place.

If I follow correctly, Pablo's original inquiry had to do with the child terms listed under Dravet, which are currently two OMIM terms associated with two specific genes, GABRA1 and STXBP1. The experts pointed out that Dravet was a clinical diagnosis that can be caused by more than one gene. GABRA1 and STXBP1 specifically have relatively weak evidence associating them with Dravet (such as single report); further, these genes have also been associated with other clinical presentations. The group felt that it was potentially misleading to list disease terms that are specific to particular genes as children of Dravet, because they felt it might suggest that those are bona fide "causes" of Dravet, or that somehow the presentation of Dravet was unique to those genes. This method of presentation is perhaps leading to conflation of genetic causes vs. actual unique disease presentations - "EIEE19" is not a specific type of Dravet syndrome, but I am assuming it is listed as a child term because of the claim that variants in GABRA1 cause Dravet syndrome.

In summary, the ClinGen Epilepsy GCEP would recommend that the term Dravet syndrome be removed as a child of early onset epileptic encephalopathy, and added as a child of developmental and epileptic encephalopathy, as previously requested. We would also recommend the removal of EIEE19 and EIEE4 as children of Dravet.

@ihelbig , please chime in if I misrepresented anything. We also discussed inviting the MONDO team (and any other interested parties) to our monthly Neurodevelopmental Clinical Domain Working Group meeting (4th Tuesdays at 10C/11E) to discuss this and any other issues further. If this is something that would interest people, let me know which Tuesday might work (6/23, 7/28, etc.) and I'll make sure all relevant parties on our end can attend.

I hope that helps - sorry it is so lengthy. -Erin

[nicolevasilevsky]

Hi @ErinRiggs Thanks so much for the feedback! I will look more closely but wanted to quickly respond that yes - I'd be happy to attend your WG meeting. I am available during that time slot all summer.

[nicolevasilevsky]

related to https://github.com/monarch-initiative/mondo/issues/332

[nicolevasilevsky]

@ErinRiggs sorry I missed your previous request to make 'developmental and epileptic encephalopathy' a parent of Dravet syndrome. I created a new ticket #1637 with our action items for this class and addressed it on a PR (#1638).

I think this ticket can be closed.

[nicolevasilevsky]

@ErinRiggs I should note too, we removed the children of Dravet syndrome already (you should be able to see that in the current released version of Mondo)

Thank you for your feedback!