Genotype-level quality control substantially reduces error rates in population-scale whole-genome sequencing Population-scale whole-genome sequencing data will contain many individual-level genotype errors, even after allele-level quality control (QC). We establish the need for genotype-level QC using UK Bio...

New paper on everyone’s favourite topic, QC!
We show why you should do genotype-level QC on your WGS data

www.biorxiv.org/content/10.1...

Very real quotes about this paper -
“The most exciting, mind-blowing paper of the year!”
“On a par with Fisher 1918”
“I read it every night. Just so beautiful”

Modulating splicing in five prime untranslated regions to treat rare haploinsufficient disease Rare genetic disorders collectively impact over 300 million people worldwide, yet around 95% have no specific treatments. For the many rare disorders caused by haploinsufficiency, effective therapies ...

*A new pre-print on increasing gene expression!* 🧬📈

doi.org/10.64898/202...

Our new study defines a distinct #neurogenetic condition arising from recurrent structural variants at 16p13.3 palindrome.

Individuals show progressive ataxia, cognitive decline, and a characteristic MRI pattern with caudate & cerebellar atrophy.

#Genomics #RareDisease 🧵1/3

Two pie charts. On the left, a small segment of a grey pie chart labelled 'Unsolved NDD (N=7,968, 100%)' is shaded dark. A zoom out from this small segment shows individuals with new "RNU-opathies" in 100KGP (N=118, 1.48%). This has five segments, in order of size: (1) RNU4-2 dominant (N=59, 0.74%), (2) RNU2-2 recessive (N=38, 0.48%), (3) RNU2-2 dominant (N=11, 0.14%), (3) RNU4-2 recessive (N=5, 0.06%), (4) RNU5B-1 dominant (N=5, 0.06%).

I absolutely love this figure in a second paper led by Adam Jackson, @alexblakes.bsky.social, and Sid Banka (www.medrxiv.org/content/10.1...) of RNU gene diagnoses in @genomicsengland.bsky.social 100k genomes project.

(1) showing just how many new diagnoses are found across these genes ❤️

2/3

The biology here is fascinating too. Really nice to see the clustering of compound het / homozygous variants in the Sm site in your cohort for example.

Congratulations to you and the whole team on this really beautiful work. This is a really important discovery for patients and families affected by rare conditions.

This is ... just brilliant. Another ncRNA gene involved in rare developmental diseases, and these are a meaningful number of new cases - also interesting the dominance/linear/recessive differences

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...

(2) but even cooler is the flip of frequency between dominant and recessive forms in RNU4-2 and RNU2-2, driven by different signatures of mutation and selection - variants across RNU2-2 tend to be more common, driving a higher comp het frequency.

We have a lot to learn from these genes yet!!! 🧬🤓

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

Congratulations @alextremophile.bsky.social, tremendous to see this online! :)

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...

Love when you can build a paper out of a personal bugbear! tl;dr the precomputed SpliceAI scores are great, but proceed with caution!

Our Future Health: a unique global resource for discovery and translational research - Nature Medicine Our Future Health has recruited more than 1 million participants in the UK, with biobanked bloods, making it the largest consented cohort of its type in the world.

Very exciting to have access to "Our Future Health" data and begin understanding what is available and how to access it

Many thanks to the volunteers so far. Still a long way to go - consider signing up if you haven't already!

This is a greater primer on the aims www.nature.com/articles/s41...

New recessive neurodevelopmental disorder caused by RNU4-2 variants | Nicola Whiffin posted on the topic | LinkedIn I am excited to share our preprint describing a new **recessive** neurodevelopmental disorder caused by variants in the non-coding snRNA RNU4-2 🎉 https://lnkd.in/dHNDCsDe Led by two super ⭐ s Roci...

3/3 I am thrilled to be part of a study establishing the clinical phenotypes of NDD associated with recessive variants in RNU4-2. Thank you to @rociorius.bsky.social, @alexblakes.bsky.social, @cassimons.bsky.social and @nickywhiffin.bsky.social for leading this work! More details: lnkd.in/eTJ5Rapt

1st Bluesky post with recent updates:
1/3 It was incredible to attend and speak at the ReNU Hope Conference in Long Island, NY. This was the first time I met the families and the ReNU warriors, sharing many touching stories. I hope to continue advocacy in China where few are currently diagnosed.

Nuevo diagnóstico ligado a #RNU4-2 🧬: variantes bialélicas causan un #TND recesivo con cambios característicos en sustancia blanca en RM 👉 hay que considerar este gen no codificante en la búsqueda/diagnóstico.
tinyurl.com/3j9r56s8
La historia completa la cuenta @alexblakes.bsky.social aqui 🧵👇

New preprint! The outcome of a wonderful collaboration with @nickywhiffin.bsky.social’s team to define a new recessive syndrome associated with inherited variants in RNU4-2, the non-protein-coding gene that keeps on giving.

This whole thread describes how 18 months of work on this tiny piece of genome identified 2/3 new syndromes. it’s a very compelling clinical genetics story!

Saturation genome editing of BRCA1 across cell types accurately resolves cancer risk Germline pathogenic BRCA1 variants predispose women to breast and ovarian cancer. Despite accumulation of functional evidence for variants in BRCA1 , over half of reported single-nucleotide variants (...

Our latest research is out today on ‪@medrxivpreprint.bsky.social:

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

Saturation genome editing of BRCA1 across cell types accurately resolves cancer risk.

Led by the amazing Phoebe Dace. This one’s packed full of data, so check out the paper. Quick highlights… 🧵 1/n

Isn't genetics cool???

Within only 145 nucleotides(!) of a non-coding RNA (RNU4-2) - different variants in distinct regions / structures cause three distinct disorders!!! (all discovered within the last 18 months)

🤯🤓🧬❤️

Look at the insane speed of discovery around this snippet of DNA. Sometimes the machine of science is amazing. 🤩

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 ❤️

We recently performed SGE of RNU4-2 and identified functionally impactful variants underlying a new recessive disease. Today, the team led by @rociorius.bsky.social @alexblakes.bsky.social @cassimons.bsky.social & @nickywhiffin.bsky.social provide in-depth analysis of its clinical presentation. 🧵⬇️

🚨 New preprint led by amazing duo @rociorius.bsky.social and @alexblakes.bsky.social in collaboration with @cassimons.bsky.social, @dgmacarthur.bsky.social and many other amazing folks! ❤️

We describe the clinical phenotype of a recessive NDD associated with biallelic variants in RNU4-2 🧬

See 🧵👇

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...

Thanks also to the institutions whose incredible resources and platforms have made this work possible, including @ukbiobank.bsky.social, @genomicsengland.bsky.social, @manchester.ac.uk, @ox.ac.uk, as well as our funders including @wellcometrust.bsky.social.

A huge thank you to the patients and families who participated in the study, and clinical teams who contributed and made this work possible. To tag just a few collaborators from my extremely nascent Bluesky account… @christeldepienne.bsky.social @poseypod.bsky.social @anneotation.bsky.social

... and supported by @dgmacarthur.bsky.social, @gregfindlay.bsky.social, Sid Banka (@mft-imrare.bsky.social), and collaborators across the world.🌏