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Alex Geary @alextremophile.bsky.social · Aug 29

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!

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Alex Geary @alextremophile.bsky.social · Aug 29

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 👀

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Alex Geary @alextremophile.bsky.social · Aug 29

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.

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Alex Geary @alextremophile.bsky.social · Aug 29

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...

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Alex Geary @alextremophile.bsky.social · Aug 29

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.

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Alex Geary @alextremophile.bsky.social · Aug 29

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%.

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Alex Geary @alextremophile.bsky.social · Aug 29

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.

Homepage

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

www.genomicsengland.co.uk

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Alex Geary @alextremophile.bsky.social · Aug 29

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.

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Alex Geary @alextremophile.bsky.social · Aug 29

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.

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Alex Geary @alextremophile.bsky.social · Aug 29

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.

Ensembl Variant Effect Predictor (VEP)

www.ensembl.org

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Alex Geary @alextremophile.bsky.social · Aug 29

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.

SpliceAI Lookup

spliceailookup.broadinstitute.org

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Alex Geary @alextremophile.bsky.social · Aug 29

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...

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 ...

www.medrxiv.org

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Reposted by Alex Geary

alexblakes.bsky.social @alexblakes.bsky.social · Aug 18

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) ...

www.medrxiv.org

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Reposted by Alex Geary

alexblakes.bsky.social @alexblakes.bsky.social · Aug 18

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...

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) ...

www.medrxiv.org

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Alex Geary @alextremophile.bsky.social · Aug 18

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 ❤️

alexblakes.bsky.social @alexblakes.bsky.social · Aug 18

I am absolutely delighted to share our work describing a new *recessive* condition caused by variants in #RNU4-2. Yes, that #RNU4-2!

tinyurl.com/3j9r56s8
@rociorius.bsky.social @yuyangchen.bsky.social @gregfindlay.bsky.social @dgmacarthur.bsky.social @cassimons.bsky.social @nickywhiffin.bsky.social

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) ...

www.medrxiv.org

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Reposted by Alex Geary

Nechama Wieder @nechamawieder.bsky.social · Jul 4

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

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Alex Geary @alextremophile.bsky.social · Jul 4

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!

Nechama Wieder @nechamawieder.bsky.social · Jul 4

Super excited to share our new review paper - The role of untranslated region variants in Mendelian disease!
www.nature.com/articles/s41...

The role of untranslated region variants in Mendelian disease: a review - European Journal of Human Genetics

European Journal of Human Genetics - The role of untranslated region variants in Mendelian disease: a review

www.nature.com

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Reposted by Alex Geary

William Shakespeare @shakespeare.lol · Apr 25

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

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Alex Geary @alextremophile.bsky.social · Apr 25

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...

The A The C The G The T

The Rayne · Single · 2025 · 2 songs

open.spotify.com

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Reposted by Alex Geary

Dr Zoë Ayres @zjayres.bsky.social · Apr 16

Love to my trans sisters, always.

#TransRightsAreHumanRights

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Reposted by Alex Geary

the Mountain Goats @themountaingoats.bsky.social · Apr 16

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.

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Alex Geary @alextremophile.bsky.social · Apr 14

Finally, and most importantly - this would not have been possible without the support, and contributions made by all the participants and families enrolled in @genomicsengland.bsky.social, their clinical teams, and the staff at Genomics England - to whom we are eternally grateful.

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Alex Geary @alextremophile.bsky.social · Apr 14

I would like to give my heartfelt thanks to everyone who has contributed to this work, in particular the incredible @nickywhiffin.bsky.social, Alex Blakes, @drjennylord.bsky.social , Sid Banka and Scott Findlay, who have worked very hard to get this out.

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Alex Geary @alextremophile.bsky.social · Apr 14

The take 🏡 :

Variants that occur outside of protein-coding regions represent a modest but appreciable contribution to rare disease, and should be routinely incorporated into diagnostic pipelines.

(We present a systematic framework for doing this!)

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Alex Geary @alextremophile.bsky.social · Apr 14

Looking at the burden that these variants may represent in rare disease we did see an appreciable increase in variants with the potential to disrupt regulation in cases vs controls, though this did not meet the threshold for significance.
link.springer.com/article/10.1...

Two panels showing the odds ratios of burden testing results for cases vs controls across regions and annotation types. It shows an increased number of variants in case vs control participants, however this is modest, and for the KOZAK and 3' intron groups the odds ratios are wide.

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