[NTR] Microcephaly with lissencephaly and/or hydranencephaly

[Bryannavanhoute]

Preferred term label: Microcephaly with lissencephaly and/or hydranencephaly

Synonyms

Definition (free text, please give PubMed ID, if applicable, in format PMID:#######) A brain disorder caused by biallelic variants in NDE1 that is characterized by extreme microcephaly (typically head circumference of more than 10 standard deviations (SD) below the mean), profound motor and intellectual disability, spasticity, and incomplete cerebral formation. Radiologic studies demonstrate overt microcephaly with cortical dysgenesis ranging from simplification to pachygyria/lissencephaly to hydranencephaly. Agenesis of the corpus callosum as well as hypoplasia of the brainstem and cerebellum are typically present. (PMIDs 21529751, 22526350)

Parent term (use OLS, or your favorite ontology browser) Microcephaly MONDO: 0001149

Children terms (if applicable) Should any existing terms that should be moved underneath this new proposed term? Lissencephaly 4 and Microhydranencephaly

Your nano-attribution (ORCID) If you don't have an ORCID, you can sign up for one here Requested by the ClinGen Brain Malformations GCEP (https://www.clinicalgenome.org/affiliation/40020/)

CC: @ErinRiggs

[sabrinatoro]

Based on the definitions, I don't think that 'lissencephaly 4' (MONDO:0013527) and 'NDE1-related microhydranencephaly' (MONDO:0011504). When these diseases include "microcephaly" among their features/symptoms, I don't know that they are "microcephaly". Also: microcephaly is a "neurodevelopmental disorder", but these terms suggested children terms are "cerebral malformation". Is that correct? Should microcephaly be a "cerebral malformation" instead of a "neurodevelopmental disorder"? @nicolevasilevsky, what do you think?

[ErinRiggs]

The experts in the Brain Malformations GCEP requested that this be considered a type of microcephaly. I am happy to connect you with one of our chairs via email, but they are not on GitHub. Let me know if you'd like me to make that connection.

-Erin

Erin Rooney Riggs, MS, CGC Assistant Professor Autism & Developmental Medicine Institute Geisinger @.***

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Based on the definitions, I don't think that 'lissencephaly 4' (MONDO:0013527) and 'NDE1-related microhydranencephaly' (MONDO:0011504). When these diseases include "microcephaly" among their features/symptoms, I don't know that they are "microcephaly". Also: microcephaly is a "neurodevelopmental disorder", but these terms suggested children terms are "cerebral malformation". Is that correct? Should microcephaly be a "cerebral malformation" instead of a "neurodevelopmental disorder"? @nicolevasilevskyhttps://nam12.safelinks.protection.outlook.com/?url=https%3A%2F%2Fgithub.com%2Fnicolevasilevsky&data=05%7C01%7Ceriggs%40geisinger.edu%7C4ca41af0cfaf47d4ef0108dac1e50424%7C37d46c567c664402a16055c2313b910d%7C0%7C0%7C638035486621071600%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=mFNzgmqe%2FDqAAgmkvXyqX6trcbe8s%2Fiv79VDFzHVtRg%3D&reserved=0, what do you think?

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[nicolevasilevsky]

Hi @ErinRiggs discussing with the experts over email sounds like the best next step, thank you!

[nicolevasilevsky]

per email, I think this is what we want:

yellow= new class

[sabrinatoro]

For the record (relevant information from the email - copied and pasted)

• As a recap, the reason we chose to create a new term is that the severe microcephaly in NDE1 altered subjects is associated with a range of malformations ranging from simplification to lissencephaly to hydranencephaly/destruction which we lumped together because there was not a clear genotype-phenotype relationship. (There is also a Paciorkowski paper where they assert polymicrogyria in 1 case but I don’t know how conclusive that is based on the quality of the images they submitted which are fairly noisy, attached, though that did not prevent a Dobyns co-authored paper from listing NDE1 as a PMG gene.) We also seek to avoid the term “microlissencephaly” as it has a confused history (variably requiring measured cortical thickness) and we typically do not have the ability to accurately determine whether the cortex is thick based on submitted images in papers. So I would go with the following definition of “Microcephaly with lissencephaly and/or hydranencephaly”: A brain disorder caused by biallelic variants in NDE1 that is characterized by extreme microcephaly (typically head circumference of more than 10 standard deviations (SD) below the mean), profound motor and intellectual disability, spasticity, and incomplete cerebral formation. Radiologic studies demonstrate overt microcephaly with cortical dysgenesis ranging from simplification to pachygyria/lissencephaly to hydranencephaly. Agenesis of the corpus callosum as well as hypoplasia of the brainstem and cerebellum are typically present.
• I am not sure what is permissible for the MONDO ontogeny trees with regards to cross referencing. I was thinking maybe it would make sense for this new term to be under microcephaly, but it looks like the listed options are either pure primary microcephalies or can present that way. So unless someone else has suggestions otherwise, I think your suggestion of placing the new term in the location of lissencephaly 4 and NDE1-related microhydranencephaly sounds reasonable. Those existing terms could be subordinated to the new term as far as I am concerned because I am assuming they were created at someone’s request already.
• (about microencephaly as a parent): my sense is that microcephaly is accurate but doesn't fully capture the phenotype=-hence, the other terms being considered.

Question: Based on the definitions, we are unsure if 'lissencephaly 4' (MONDO:0013527) and 'NDE1-related microhydranencephaly' (MONDO:0011504) are a type of Microcephaly with lissencephaly and/or hydranencephaly. While these diseases include "microcephaly" among their features/symptoms, I don't know that they are a "microcephaly". In an ontology, any child term must inherit all of the features of the parent term. Also: microcephaly is a "neurodevelopmental disorder", but this ticket suggests that the children terms are "cerebral malformation". Is that correct? Should microcephaly be a "cerebral malformation" instead of a "neurodevelopmental disorder"?

• (I am a little confused because neither of the current Mondo terms are subordinate (child term) to microcephaly currently. So the request we made would be refining the current terminology (without disposing of the old ones by subordinating the existing terms to the new ones). Microcephaly is severe in this NDE1 disorder but is not generally the only finding so I don’t know that it is mandatory to put another child term to microcephaly for NDE1 (I am agnostic). Many people would consider microcephaly a disorder of neuronal precursor proliferation and a form of malformation. It would not be unreasonable to duplicate it under the “cerebral malformation” tree though I am not sure how many times an item can be duplicated inside of the ontology.

[Bryannavanhoute]

We reviewed this ticket today and understood there to be outstanding questions, but see it has been closed. Has everything been resolved?

[nicolevasilevsky]

@sabrinatoro reopening - please let us know if everything is resolved and if yes, please close. thanks!

[sabrinatoro]

@Bryannavanhoute Thank you for checking. I believe all the questions were answered. In order for the new term to be correct ontologically, I reviewed and updated the classification of the term "microencephaly". So everything is fine, and this issue can be closed.