Alex Geary

Our final post for International Day of Women & Girls in Science is by @margotwyrwoll.bsky.social: "In my day-to-day work, I promote inclusion by mentoring early career researchers, being open about my own career path & advocating for fair recruitment and promotion processes."
#EveryVoiceInScience

MRC four-year International PhD programme: Human Genetics, Genomics and Disease | IGC Graduate Research & Training | Institute of Genetics and Cancer Applications now open.

We are looking for the last ever intake of HGU PhD students to start in September.
If you are passionate about biomedical research and are interested in doing a PhD, please apply by 11 January.
Find out more here 👉 edin.ac/4srdd6t
Apply here 👉https://edin.ac/49aBgPz

Eeep! I can’t quite believe it! ♥️

Thanks Kaitlin! ♥️

It has been a big day, full of big emotions, but the biggest is the gratitude I feel to all the members of the CRDG, past and present, especially @nickywhiffin.bsky.social, and to @jorisveltman.bsky.social and @margotwyrwoll.bsky.social for already making me feel so welcome!
🧬Exciting times ahead!👩‍💻

Photographs of Joris Veltman and Margot Wyrwoll smiling

I am SO excited to be joining the group of @jorisveltman.bsky.social where together with @margotwyrwoll.bsky.social we will focus on solving challenges in reproductive genomics and genomic medicine, and improving the lives of patients and their families.

Purple logo of the Institute of genetics and cancer

From January the first I will be taking my first steps into independence as the shiny new Lecturer in Computational Genomics, in the Institute of Genetics and Cancer (@uoe-igc.bsky.social) at the University of Edinburgh (@edinburgh-uni.bsky.social)

Photograph of Nicky Whiffin smiling in a snowy forest

In that time, under the phenomenal guidance of @nickywhiffin.bsky.social it has grown into a powerhouse of awesome science, empowerment and joy. I am devastated to be leaving, but am doing so with all the tools and support I need to succeed - a testament to Nicky's skills as a leader and mentor!

Photograph of Computational Rare Disease Genomics group at a Christmas party.

It is a big day for me : a 🧵🪡

For the last five years I have had the absolute honour of being a postdoc in the 💜INCREDIBLE🩷 Computational Rare Disease Genomics group at the Nuffield Department of Medicine (@ndm.ox.ac.uk @ox.ac.uk), Uni. of Oxford (@ox.ac.uk).

a cartoon character says you are my hero ALT: a cartoon character says you are my hero

And a special shout out to the absolutely awesome senior author on this - @ruebenadawes.bsky.social who was a total delight to work with from start to finish!

I would also like to thank all my co-authors for the time, effort and input that has made this a super little bit of work! I'm looking at you @francois-leco.bsky.social Suzi Walker and @nickywhiffin.bsky.social 👀

a man with long hair and a beard is smiling and saying thank you . ALT: a man with long hair and a beard is smiling and saying thank you .

We would like to thank everyone who has contributed to this work, but most of all the team at Genomics England, all the participants and their families, without whom all this would not have been possible.

We therefore developed a command-line tool, ‘SpliceAI-splint’, to identify the subset of variants for which the precomputed scores may have decreased accuracy, to allow reannotation of a smaller overall variant set. github.com/Computationa...

These findings have real implications for the continued use of precomputed scores. However, despite these issues, precomputed scores still have substantial utility in limiting the computational resources required to identify predicted splice-altering variants.

By correcting these issues we found an increase of 18.2% predicted splice-altering variants compared with variants identified using precomputed scores alone. When assessed using diagnostic variants, updated SpliceAI scores resulted in a diagnostic increase of 11.7%.

Homepage Genomics England analyses sequenced genomes for the NHS and then equips researchers to use data to help find the cause of disease.

To determine the potential impact of these issues we annotated variants in a subset of participants recruited with neurodevelopmental disorders in the @genomicsengland.bsky.social National Genomics Research Library, using both precomputed scores, and SpliceAI with updated parameters.

Precomputed scores were calculated using a distance parameter of 50nt, however the suggested threshold has increased to 500nt. They can’t handle larger insertions and deletions. And there are errors within the file itself, likely arising from conversion of the original annotations to GRCh38.

Unfortunately these scores have limitations that can reduce their accuracy in certain contexts: For example changes in transcript annotations, altered transcript boundaries, absence of annotated genes, and changes to exon composition can mean that scores are missed or altered.

These scores also underlie spliceAI annotations in many variant effect predictors such as the @ensembl.org VEP, forming the basis for annotation in many diagnostic pipelines.

SpliceAI is an invaluable tool to identify splice-altering variants. The provision of precomputed scores for all theoretically possible SNVs, 1 base insertions, and 1-4 base deletions has extended this further, massively reducing the time and cost associated with running spliceAI directly.

Using SpliceAI to triage splice-altering variants in 7,220 individuals with rare conditions highlights limitations of the precomputed scores Background: SpliceAI is a deep learning algorithm that predicts whether genetic variants are likely to affect splicing. Precomputed spliceAI predictions for all theoretical SNVs and small indels were ...

I am super proud to present our new manuscript “Using SpliceAI to triage splice-altering variants in 7,220 individuals with rare conditions highlights limitations of the precomputed scores”
www.medrxiv.org/content/10.1...

Biallelic variants in the non-coding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes Genetic variants in RNU4-2, which encodes U4, a key non-coding small nuclear RNA (snRNA) component of the major spliceosome, were recently shown to cause a prevalent neurodevelopmental disorder (NDD) ...

I learned so much from this work and I hope that and discoveries like this can make a real difference to the lives of people living with #RareConditions. Please do share! 😊
www.medrxiv.org/content/10.1...

Biallelic variants in the non-coding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes Genetic variants in RNU4-2, which encodes U4, a key non-coding small nuclear RNA (snRNA) component of the major spliceosome, were recently shown to cause a prevalent neurodevelopmental disorder (NDD) ...

The headlines?

1) Variants on both copies of #RNU4-2 cause a recessive neurodevelopmental disorder with prominent speech delay
2) One of the hallmarks is distinct white matter changes on MRI
3) It is clinically and genetically distinct from #ReNU syndrome

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

An awesome piece of work by @alexblakes.bsky.social, @rociorius.bsky.social, @nickywhiffin.bsky.social and team!

I am super excited to see more emerging from this tiny, but mighty gene, and am overjoyed at the implications this has for the rare disorders community ❤️

3/
The review outlines how UTR variants cause disease, such as:
- Create or remove upstream AUGs (uAUGs)
- Alter splicing
- Alter polyadenylation
- Interfere with miRNA or protein binding

This is such an awesome review paper from @nechamawieder.bsky.social!
UTRs are more than just 'buffers' for the coding sequence - they contain a wealth of important regulatory features!

You seem’d of late to make the law a tyrant

The A The C The G The T The Rayne · Single · 2025 · 2 songs

Want a Friday mood boost whilst also raising awareness of rare disorders? Then this fresh drop from the band of one of the GEL participant panel members is for you! ♥️🎶♥️
Play it loud, share it widely!
(Beware - it is _extremely_ catchy!)

open.spotify.com/album/1f2CAX...

Love to my trans sisters, always.

#TransRightsAreHumanRights

if you are a cis person it costs you nothing to just say today that you see & hear your trans sisters & brothers & others over in the UK today -- and around the world, too, knowing that rulings like today's ripple out in ugly ways.