AFG3L2-related optic atrophy and/or ataxia

[wchankey]

Preferred gene-related syndrome label
AFG3L2-related optic atrophy and/or ataxia

Synonyms
N/A

Parent term (use OLS, or your favorite ontology browser)
hereditary optic atrophy (https://www.ebi.ac.uk/ols4/ontologies/mondo/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FMONDO_0043878?lang=en)
mitochondrial DNA depletion syndrome (https://www.ebi.ac.uk/ols4/ontologies/mondo/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FMONDO_0018158?lang=en)
autosomal recessive spastic ataxia (https://www.ebi.ac.uk/ols4/ontologies/mondo/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FMONDO_0017847?lang=en)

Definition
Any optic atrophy and/or ataxia in which the cause of the disease is a heterozygous variant or biallelic variants in the AFG3L2 gene.

**Definition source (Please give PubMed ID, if applicable, in format PMID:#######)
PMID:32219868

Children terms (if applicable) Should any existing terms be re-classified as children underneath this new proposed term?
optic atrophy 12 (MONDO:0033549)
spastic ataxia 5 (MONDO:0013776)

Your nano-attribution (ORCID) or URL for a working group
Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel (https://clinicalgenome.org/affiliation/40077/#:~:text=The%20Glaucoma%20and%20Neuro%2DOphthalmology,includes%20inherited%20optic%20atrophies%2Fneuropathies.)

AFG3L2_evidence_summary.docx

[sagehrke]

Dear @wchankey,
Thank you for reaching out to the Mondo Disease Ontology, part of the Monarch Initiative!

We have received your ticket and will review it as soon as possible.

If you have any additional information or updates relevant to your inquiry, please add them in a comment on this ticket. Your input is valuable in helping us understand and resolve the issue effectively.

Thank you for your patience and for your contributions to Mondo!

Sincerely,
The Mondo Team

[wchankey]

Thank you Sarah! I'll don't have any additional info or updates to add at the moment, but appreciate the chance to add them to this ticket if anything comes up. I'll also be happy to research anything or be a contact person if you think of any questions for the ClinGen Glaucoma and Neuro-Ophthalmology GCEP. Thanks for your message and your time to consider this request!

[yshwetar]

Hi @nicolevasilevsky!

@sabrinatoro and I have been discussing this issue at length on slack. Per the submitted issue and the attached word document, this disease exhibits a spectrum of phenotypes, including spastic ataxia, optic atrophy, and being a mitochondrial depletion syndrome. According to the literature in the aforementioned word document and other published articles, only some presentations of the disease have optic atrophy and or spastic ataxia, while ALL presentations of this disease have a basis in mitochondrial depletion. Given these considerations, sabrina and I think:

1. Have this be a child of only "mitochondrial DNA depletion", and not Optic Atrophy or Spastic Ataxia, as it does not ALWAYS exhibit Optic Atropy and or Spastic Ataxia
   2b. Given this is a clingen working group providing the information, we will follow their expertise and use the label of "AFG3L2-related optic atrophy and/or spastic ataxia".
   2a. It would be best to include the synonym: "AFG3L2-related mitochondrial DNA depletion syndrome"
2. Definition: "A mitochondrial DNA depletion syndrome in which the cause of the disease is a heterozygous variant or biallelic variants in the AFG3L2 gene. The disorder is characterized by a spectrum of phenotypes (or features) including optic atrophy and/or ataxia"
3. Optic Atrophy 12 and Spastic Ataxia 5 as children of this new term

Let us know what you think of our deliberations, and thank you!

[wchankey]

Hi Sarah and Sabrina,

Thank you so much for considering this AFG3L2 request and for taking the time to discuss it and get the ontology just right! The ClinGen group that I work with would agree that mitochondrial dysfunction seems to underlie both optic atrophy 12 and spastic ataxia 5 (based on evidence from some of the published cases), so it's an interesting idea to consider "mitochondrial DNA depletion" as the unifying phenotype among all of these cases with AFG3L2 loss-of-function. One reason our group didn't think of this as a disease name option might be that mitochondrial network fragmentation has been shown/confirmed for only a small proportion of cases from each type. But I see your point that this might be a better choice of unifying feature than either "optic atrophy" or "spastic ataxia", each of which have been confirmed to be absent from some proportion of cases (at least at the time of diagnosis). I like the definition you drafted for "AFG3L2-related mitochondrial DNA depletion syndrome".

I was wondering if you would like feedback on anything from the ClinGen Glaucoma / Neuro-Ophthalmology folks? Or if you have any lingering clinical questions to ask? If so, am happy to run an idea or a question by them. Or if you feel it's all set to go from an ontology perspective, that works too! Thanks so much for your time and for keeping me in the loop!

William

[sabrinatoro]

Hello @wchankey
Thank you for your feedback.
And yes, please, check with your team to make sure they are aware of our plans and are fine with it. If you have any questions regarding the ontology modeling choices (e.g why the term cannot have all the parents you suggested), please let us know.

With regards to the definition including "mitochondrial DNA depletion syndrome":
Our reasoning came from the fact that your requested "mitochondrial DNA depletion syndrome" as a parent. Therefore we assumed that the term was a type of mitochondrial DNA depletion syndrome. However, if it is not the case, or if you don't know, or if it is not 100% cases true, we should go up in the ontology (for both the parent term and the definition) and use a more general term instead 'inborn mitochondrial metabolism disorder' (MONDO:0004069) or 'mitochondrial disease' (MONDO:0044970). We could also go much higher in the ontology and use the parent "hereditary disease" (MONDO:0003847)

Please let us know if you have questions. We are also happy to have a quick meeting with you and your team if it is easier. Just let us know. Thank you!

[wchankey]

Hi Sabrina and Sarah,

Sorry for my late reply. I prepared a couple of slides (
AFG3L2_Mondo_question.pptx
) to ask the ClinGen Glaucoma group for feedback on your idea for how to re-organize the AFG3L2-related ontology, but I didn't have an opportunity to ask them at their recent meeting. I was wondering if you might have a chance to review the slides and confirm that i correctly understood your idea (shown on slide 2)? Slide 1 also shows the current Mondo architecture, which is where we got the idea to include "mitochondrial DNA depletion syndrome" as a parent term. Anyways, if your proposal matches what's shown on slide 2 or is similar to it, I suspect the ClinGen Glaucoma folks will agree that this sounds like a good solution. Thank you for your time!

William

[yshwetar]

Hi William,

Overall the slides look excellent - We just ask that for bullet point 2. of the "additional notes and explanation" slide, you say that the label should be "AFG3L2-related mitochondrial DNA depletion syndrome", with synonym "AFG3L2-related optic atrophy and/or spastic ataxia". Otherwise nothing else needs to be modified! Thank you.

Yousif

[wchankey]

Hi Yousif,

Thank you for reviewing the slides. I can definitely revise the second bullet point on the "additional notes and explanation" slide as you suggested.

I was wondering if that means the new Mondo term will be "AFG3L2-related mitochondrial DNA depletion syndrome", with "AFG3L2-related optic atrophy and/or spastic ataxia" only listed as its synonym but not created as a new term?

The reason I ask is that for the purposes of gene curation, the group I work for has discussed and approved "AFG3L2-related optic atrophy and/or spastic ataxia" as a term that would reflect the published cases well. They would probably agree with "AFG3L2-related mitochondrial DNA depletion syndrome" as a secondary synonym. Since loss of mitochondrial DNA is something seen in animal models. But I have not found any published human cases so far with confirmed mitochondrial DNA depletion (only a small number with confirmed mitochondrial network fragmentation). So although mitochondrial DNA depletion is probably suspected, I might need to consult the group for troubleshooting if the "AFG3L2-related mitochondrial DNA depletion syndrome" were the primary term.

Thank you for reviewing the slides and for any further information or advice you might have!

Best,
William