Christel Depienne

😂

snRNAs indeed everywhere 😱😂

It represents the PhD work of Pierre Tilliole (Godin lab) and Carolin Mattausch (my group) with the contribution from Elsa Leitão .

Many thanks to all 3 of them, to Juliette, to all families who participated, clinicians and all collaborators who made this long-term effort possible. 🙏

These results highlight functional retrocopies as an overlooked layer of genetic robustness and evolutionary innovation in mammalian brain development.

This study is the result of >10 years of work in my group, in close collaboration with Juliette Godin’s group at IGBMC, Strasbourg.

🧠Pathogenic RBMX variants perturb cortical development through both partial loss-of-function and gain-of-function mechanisms.

🐁Mice possess two Rbmxl1 retrocopies that arose independently from the human RBMXL1. Rbmx-deficient mice exhibit unexpectedly mild cortical phenotypes mirroring the defects seen in patients, likely due to better compensation by Rbmxl1.

👯‍♂️RBMX and RBMXL1 are both expressed during brain development, share protein and RNA partners and function, and act redundantly during corticogenesis.

🧬RBMX has a close autosomal retrocopy, RBMXL1, sharing ~95% sequence identity with RBMX in humans

🧬Hemizygous RBMX variants on chromosome X cause neurodevelopmental disorders in males, with intellectual disability, microcephaly, brain malformations, and microphthalmia.

Using human genetics and complementary ex vivo, in vitro, and in vivo functional approaches, we uncover a critical role for the RBMX retrocopy, RBMXL1, in brain development, possibly also modulating the phenotype associated with pathogenic RBMX variants.

RBMX functional retrocopy safeguards brain development Retrotransposition has generated thousands of intronless gene copies in mammalian genomes, yet their contribution to brain development and evolution remains largely unexplored. Here we uncover a criti...

I am delighted to finally share our new preprint exploring the role of RBMX and its retrocopies in neurodevelopment:

👉🏻Read the full preprint here:

www.medrxiv.org/content/10.1...

Below are the key findings 👇🏻

Congrats to you as well!
Amazing to see how different approaches led to outcomes that are both similar and wonderfully complementary 😊

While I was taking a holiday last week, 2 super exciting preprints dropped, adding to another posted 6 days prior.

These papers describe a remarkable role for *recessive* variants in *RNU2-2* causing developmental and epileptic encephalopathy

🧵 by the amazing @christeldepienne.bsky.social 👇

1/3

Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption - Nature Genetics Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathog...

Link to
Our previous article: www.nature.com/articles/s41...

Elsa Leitao
Amandine Santini
Benjamin Cogne
Myriam Essie
Clément Charenton
Camille Charbonnier
Gaetan Lesca
Caroline Nava
@hcmefford.bsky.social @nickywhiffin.bsky.social
@cwlaflamme.bsky.social
And many many others

This study brought together >200 collaborators worldwide and would not have been possible without the contribution of the Plan France Médecine Génomique (PFMG). 🙏

Biallelic variants in RNU2-2 cause a remarkably frequent developmental epileptic encephalopathy Neurodevelopmental disorders (NDDs) affect 2-4% of the population, are predominantly genetic, and remain unsolved in ~50% of individuals. We show that rare biallelic variants in RNU2-2 are enriched an...

Importantly, these findings are independently supported by two other preprints, including one posted the exact same day:
📄 www.medrxiv.org/content/10.1...

Transcriptomic and DNA methylation analyses showed subtle, variant-specific effects on splicing and episignatures.
Our results support a continuum between dominant and recessive disorders and establish RNU2-2 DEE as nearly as frequent as ReNU syndrome (RNU4-2),

Remarkably, recessive RNU2-2 DEE is at least twice as common as the dominant form.
It often arises from a de novo variant in trans with an inherited allele, reflecting the high mutability of snRNA genes.

We analyzed 200 potentially functional spliceosomal snRNA genes in 26,911 individuals with rare disorders.
This revealed de novo (dominant) or biallelic (recessive) RNU2-2 variants in 126 individuals from 108 families.

Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies Variants in spliceosomal small nuclear RNA (snRNA) genes RNU4-2 (ReNU syndrome), RNU5B-1 , and RNU2-2 have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, prev...

After our study on RNU4-2 and RNU5B-1 published in May (Nava et al, Nature Genetics 2025), I am excited to share our new preprint reporting dominant and recessive variants in RNU2-2 as a frequent cause of developmental and epileptic encephalopathy (DEE).

📄 www.medrxiv.org/content/10.1...

Today, the Scientific Programme Committee wrapped a fantastic and exciting programme for #eshg2026 conference! More information will available on our conference website soon. We look forward to welcoming you in Gothenburg!

It's time!!!

An entire session of #eshg2025 on snRNA genes ❤️🤓

Next up: Amandine Santini

International study led by
@christeldepienne.bsky.social
145 ReNU syndrome individuals- T-loop variants associated with higher phenotypic severity and more 5'splice site disruption (19 cases).

35 cases/45 controls - identify a shared episignature.

#eshg2025 1/2

Driven by the absolutely incredible families - it is truly amazing and humbling to watch!!

Meet some of them here: www.renusyndrome.org/renu-hope-vi...

❤️🥹

@anneotation.bsky.social @dgmacarthur.bsky.social @christeldepienne.bsky.social #renuCrew

Saturation genome editing of RNU4-2 reveals distinct dominant and recessive neurodevelopmental disorders Recently, de novo variants in an 18 nucleotide region in the centre of RNU4-2 were shown to cause ReNU syndrome, a syndromic neurodevelopmental disorder (NDD) that is predicted to affect tens of thous...

🚨I could not be more excited to share our new preprint on saturation genome editing of the small nuclear RNA (snRNA) RNU4-2:
www.medrxiv.org/content/10.1...

A super fun collaboration with incredible duo @gregfindlay.bsky.social @joachimdejonghe.bsky.social from @crick.ac.uk
🧬🖥️🩺

🧵1/12

We report a new configuration of repeat expansion in MARCHF6 (FAME3) consisting in elongated TTTTA repeats and only 5-11 TTTCA. This expansion segregates in two unrelated families with myoclonus without epilepsy.

Happy to share our latest research article published open access in movement disorders movementdisorders.onlinelibrary.wiley.com/doi/epdf/10....

One more week until the abstract submission deadline for #eshg2025 #hybridconference! Do not forget to submit your abstract until Thursday, January 30, 2025, 23.59 h CET. All information can be found on our website:
2025.eshg.org/abstracts/
#genetics #genomes

I've updated the starter pack for rare genetic epilepsies 🧠🧬

It is a work in progress and I will continue to update the pack over the coming weeks 🤩

go.bsky.app/NXw4e8C