Tom Wright

1/ #SantaScience 🎅🧵

🐥1st Bluesky Rodeo
🔄💬X cross-post

A year ago today @theguardian.com featured our festive research

🔎We discovered Santa has a facial #phenotype distinct from elderly bearded men

💗Evidence #Santa is real

📰 www.theguardian.com/lifeandstyle...

📝 pubmed.ncbi.nlm.nih.gov/36548933

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

Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia - PubMed Complex neurodegenerative conditions have occasionally been associated with copy-number gains. Using microarray and genome sequencing on DNA samples from eleven individuals from nine unrelated families, we show that copy-number gains at 16p13.3 cause a severe, recognizable disorder characterized by …

Very grateful to colleagues including @rdexeter.bsky.social, @nihrexeterbrc.bsky.social, @stefanbarakat.bsky.social, the NHS Rare & Inherited Disease Genomic Network of Excellence, and to the patients and families who made this work possible. 🙏

Paper: pubmed.ncbi.nlm.nih.gov/41349538/

another great international collaboration with our friends in UK and Australia to which we could contribute, describing a very unique disease mechanism for a novel neurodegenerative disorder #genetics #raredisease @ajhgnews.bsky.social @jamesfasham.bsky.social @rdexeter.bsky.social

Collaborative science in genomics: The value of data sharing and thoughtful stewardship Large-scale data sharing is indispensable for advancing human genetics and genomics (HGG) research and medicine. The willingness of study participants and researchers to share data has been the…

📊Large-scale data sharing is indispensable for human genetics & genomics. ASHG calls for a broad data-sharing ethos and responsible stewardship that protects participants while enabling collaboration.
#HumanGenetics #OpenScience

www.cell.com/ajhg/fulltex...

Yesterday, our Chair and Secretary presented the latest ESHG-Young activities at the ERN-ITHACA Board Meeting 🧬
Great chance to show how we connect early-career human geneticists across Europe 🌍 and to recruit please for our next matchmaking at ESHG Gothenburg 🤝
#ERNITHACA #ESHGYoung #ESHG

What do we mean by "actionability" in genomic medicine? An important question as we think more about using genomes for screening as well as diagnosis... read our new paper @gimjournal.bsky.social, authors.elsevier.com/a/1mBYc3vlFV...

More international collaborative work:
Single nucleotide variants in UNC13C associated with neurodevelopmental disorders affect ethanol sensitivity in Drosophila #raredisease #morbidgene #genetics #diseasemodelling www.sciencedirect.com/science/arti...

Ensembl 2026 Abstract. The Ensembl project (https://www.ensembl.org) is a public and open resource providing access to genomes, annotations, high-quality tools, and met

Our Ensembl 2026 paper is out!
Learn about 1,900+ new genomes, expanded pangenome support, new regulation interfaces, and what’s coming in our 2026 releases.
doi.org/10.1093/nar/gkaf1239

OpenSAFELY team awarded Queen Elizabeth Prize for Higher and Further Oxford’s OpenSAFELY team wins the prestigious Queen Elizabeth Prize for revolutionising secure NHS data research, protecting patient privacy while unlocking life-saving health insights.

I'm delighted to say we have won the Queen Elizabeth Prize for Education with our work on OpenSAFELY, inventing new methods that let researchers analyse NHS GP data while protecting everyone's privacy, and with complete transparency, in a hugely productive platform!
www.ox.ac.uk/news/2025-11...

🧠🧲 BRAIN-MAGNET: A functional genomics atlas for interpretation of non-coding variants

💡 Fantastic initiative from the Barakat Lab

👀 Great to have a sneak peak at #MDC25

🧬 Predicts enhancer activity from DNA sequence

🕵️‍♂️ Prioritises functional non-coding variants

👇🧵 Check it out

BRAIN-MAGNET: A functional genomics atlas for interpretation of non-coding variants BRAIN-MAGNET, a convolutional neural network trained on 148,198 functionally tested non-coding regulatory elements, predicts enhancer activity directly from DNA sequence and identifies nucleotides ess...

Very pleased to share our latest paper published in Cell:
BRAIN-MAGNET: A functional genomics atlas for interpretation of non-coding variants: Cell www.cell.com/cell/fulltex...
@cellpress.bsky.social, @cp-cell.bsky.social, @ruizhideng.bsky.social #enhancer
here is a thread about our findings:

So proud of the wonderful progress in the specialty and my colleagues in Manchester who contributed great science and organised this event

📸 Photo of Prof Bert Callewaert presenting at the 20th Manchester Dysmorphology and Developmental Disorders Conference during Oral Presentations F: Vascular and Connective Tissue. 🗣️ Title of this talk was: “An integrative machine learning approach to classify cutis laxa patients, supported by electron microscopy.” 🎆 The slide depicted shows a clinical diagnostic framework for cutis laxa, including a sequential classification algorithm and multiple electron microscopy panels illustrating characteristic ultrastructural findings across diagnostic subgroups. The slide also displays the EpiSign (epigenetic signature analysis) and GastaltMatcher (facial phenotype analysis) logos, informing the diagnostic classification workflow.

📸 Photo of Prof Meena Balasubramanian, Professor of Medical Genetics at the University of Sheffield and Honorary Consultant Clinical Geneticist at Sheffield Clinical Genetics Service, presenting at the 20th Manchester Dysmorphology and Developmental Disorders Conference during Oral Presentations F: Vascular and Connective Tissue. 🗣️ Title of this talk was: “Changing Landscape: Advancing Diagnostics in Rare CTDs” 🎆 The slide depicted shows the title slide of the talk over a bright blue background featuring zebrafish illustrations, alongside the logos of the University of Sheffield, Sheffield Children's NHS Foundation Trust, and Bateson Centre for Disease Mechanisms. A link to Prof Balasubramanian’s University page is also presented, signposting audience to the laboratory website and research group.

📸 Photo of Dr Stefan Barakat presenting at the 20th Manchester Dysmorphology and Developmental Disorders Conference during Oral Presentations G: Developmental Epileptic Disorders. 🗣️ Title of this talk was: “SETD1B variants drive neurodevelopmental disorders and epilepsy: delineation of the clinical phenotype of more than 120 patients and insights from 2D and 3D human models” 🎆 The slide depicted is titled “Goals of Barakat lab in a nutshell”: 1. Understanding unknown causes of disease and the role of non-coding genome in neurogenetic disorders 2. Building bridges behveen the clinic research and diagnostic, leading to patient benefit in the field of neurogenetics 
The slide includes other images including pathway schematics, Clinical Genetics and Erasmus MC logos.

📸 Photo of Dr Elizabeth VanSickle of Corewell Health Helen DeVos Children's Hospital and the International Center for Polyamine Disorders, presenting at the 20th Manchester Dysmorphology and Developmental Disorders Conference during Oral Presentations G Developmental Epileptic Disorders session 🗣️ Title of this talk was: "All pediatric patients with Bachmann-Bupp syndrome treated with repurposed Eflornithine demonstrate clinical and biochemical improvement” 🎆 The slide depicted highlights BABS/ODC1 patients 20 and counting and encourages clinicians to check patient logs, check databases, and ask colleagues to contact the specialist team as "THERE IS TREATMENT”.

Day 3 at #MDC25 was fantastic 👏

F: 🩻 Vascular and Connective Tissue

G:🧠 Developmental Epileptic Disorders

H: 👥 Phenotyping and Cohort Studies

🧬💭🥘🎸🪩

On to Day 4! 🎬

📸👨‍⚕️ Photo of Prof Andrew Jackson from the University of Edinburgh taken at the 20th Manchester Dysmorphology and Developmental Disorders Conference. This was the first talk in oral presentations C on Day 2. The Session was title “Epigenomics of Rare Diseases (Symposium for Rare Disease Research UK EpiGenRare MRC Node)” 🗣️ Title of this talk was: “A novel segmental ageing syndrome demonstrates DNA methylation causes multiple age-related pathologies” The photo depicts Prof Jackson delivering the conclusion of the talk, which states: “DNA hypermethylation causes age-related pathologies”. The slide includes a scatter plot with “DNA methylation age” on the Y axis and “chronological age” on the X axis, showing that CpG methylation changes strongly correlate with chronological ageing. This conclusion followed the description of a novel segmental ageing syndrome caused by gain-of-function variants in DNMT3A, characterised by a phenotype that mimics aspects of ageing with associated DNA methylation changes.

📸👨‍⚕️Photo of Dr Adam Jackson presenting at 20th Manchester Dysmorphology and Developmental Disorders Conference in “The Non-coding, Regulatory and Genomic Disorders” session. 📖🗣️ The opening slide featured a quote from Arthur Conan Doyle (1892): “It has long been an axiom of mine that the little things are indefinitely the most important”, setting the scene for the story that followed: the discovery of RNU2-2 and RNU5B-1 neurodevelopmental disorders, caused by pathogenic variants in two “small” major spliceosomal RNA genes, collectively termed RNUpathies. 🔗📄 https://www.nature.com/articles/s41588-025-02209-y

📸👨‍⚕️Photo of Dr Alex Blakes presenting at 20th Manchester Dysmorphology and Developmental Disorders Conference in “The Non-coding, Regulatory and Genomic Disorders” session. 🗣️ Title of this talk was: “Biallelic variants in the non-coding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes” 🎆 The slide depicts the conclusions of the talk: 1) An SGE (Saturation Genome Editing) assay highlights a novel autosomal recessive neurodevelopmental syndrome in RNU4-2 2) Cystic white matter changes are a key feature 3) The U4-2:U4-1 ratio is a potential diagnostic biomarker 4) Dominant and recessive disorders in RNU4-2 are genetically, clinically, and molecularly distinct 📰 👉 Preprint available at the following link: https://www.medrxiv.org/content/10.1101/2025.08.13.25333306v1

📸👨‍⚕️Photo of Dr Pamela Bowman Senior Clinical Lecturer and SpR in Clinical Genetics in Exeter, presenting at 20th Manchester Dysmorphology and Developmental Disorders Conference in “Metabolic and Endocrine Disorders” session. 🗣️ Title of this talk was: “Early initiation of sulphonylurea therapy improves neurodevelopmental outcomes in individuals with KCNJ11-related iDEND syndrome (developmental delay, epilepsy and neonatal diabetes)” 🎆 The slide depicts three “Draw a man” tasks, each performed by individuals with KCNJ11-related iDEND syndrome that received sulphonylurea (SU) therapy at different ages (drawn aged 9, SU in utero; drawn aged 16, SU aged 4; drawn aged 22; SU aged 17) alongside the caption “NVIQ highest (70) in individual also treated with glibenclamide in utero” 📰 👉 Publication available at the following link: https://diabetesjournals.org/care/article/48/2/e10/157632

Day 2 at #MDC25 did NOT disappoint 👏

C:⚕️🧬 Epigenomics of Rare Diseases (EpiGenRare Symposium) rdrukhub.bsky.social

D: 🔀➰ Non-coding, Regulatory and Genomic Disorders

E: 🏥🩺 Metabolic and Endocrine Disorders

🥐☕️🤓🍲

On to Day 3! 🔭

Black and white drawing contrasting two scientific mindsets. On the left, a large man labelled "Lumpers" hugs a bundle of small logs tied together as one group. On the right, a thin man labelled "Splitters" chops a single large log into many small pieces with an axe. Victor A McKusick described these concepts in the paper "On lumpers and splitters, or the nosology of genetic disease" (Perspectives in Biology and Medicine, 1969)

Photo of Dr Miguel del Campo giving a talk titled: "The Fetal Fentanyl syndrome – delineation of the phenotype in 37 infants prenatally exposed to fentanyl This was during Oral Presentation B session "Environment, Exposures, and Imprinting” at the 20th Manchester Dysmorphology and Developmental Disorders Conference. Dr del Campo stands at the lectern with the presentation slide projected behind him, showing the 1973 Lancet paper describing fetal alcohol syndrome.

Day 1 at #MDC25 delivered 👏

A: 🧩🪵 Lumping, Splitting and Allelic Disorders

B: 🤰🏼🧠 Environment, Exposures and Imprinting

☕️💬

☁️2️⃣3️⃣🥂

On to Day 2! 🧬🔬

20th Manchester Dysmorphology and Developmental Disorders Conference opened with a warm welcome from @mft-imrare.bsky.social clinical director Prof Banka

Celebrating the history of the conference, we were treated to a glimpse of the original 1984 programme curated by @ddysmo.bsky.social 👑🧬

#MDC25

A table showing profit margins of major publishers. A snippet of text related to this table is below. 1. The four-fold drain 1.1 Money Currently, academic publishing is dominated by profit-oriented, multinational companies for whom scientific knowledge is a commodity to be sold back to the academic community who created it. The dominant four are Elsevier, Springer Nature, Wiley and Taylor & Francis, which collectively generated over US$7.1 billion in revenue from journal publishing in 2024 alone, and over US$12 billion in profits between 2019 and 2024 (Table 1A). Their profit margins have always been over 30% in the last five years, and for the largest publisher (Elsevier) always over 37%. Against many comparators, across many sectors, scientific publishing is one of the most consistently profitable industries (Table S1). These financial arrangements make a substantial difference to science budgets. In 2024, 46% of Elsevier revenues and 53% of Taylor & Francis revenues were generated in North America, meaning that North American researchers were charged over US$2.27 billion by just two for-profit publishers. The Canadian research councils and the US National Science Foundation were allocated US$9.3 billion in that year.

A figure detailing the drain on researcher time. 1. The four-fold drain 1.2 Time The number of papers published each year is growing faster than the scientific workforce, with the number of papers per researcher almost doubling between 1996 and 2022 (Figure 1A). This reflects the fact that publishers’ commercial desire to publish (sell) more material has aligned well with the competitive prestige culture in which publications help secure jobs, grants, promotions, and awards. To the extent that this growth is driven by a pressure for profit, rather than scholarly imperatives, it distorts the way researchers spend their time. The publishing system depends on unpaid reviewer labour, estimated to be over 130 million unpaid hours annually in 2020 alone (9). Researchers have complained about the demands of peer-review for decades, but the scale of the problem is now worse, with editors reporting widespread difficulties recruiting reviewers. The growth in publications involves not only the authors’ time, but that of academic editors and reviewers who are dealing with so many review demands. Even more seriously, the imperative to produce ever more articles reshapes the nature of scientific inquiry. Evidence across multiple fields shows that more papers result in ‘ossification’, not new ideas (10). It may seem paradoxical that more papers can slow progress until one considers how it affects researchers’ time. While rewards remain tied to volume, prestige, and impact of publications, researchers will be nudged away from riskier, local, interdisciplinary, and long-term work. The result is a treadmill of constant activity with limited progress whereas core scholarly practices – such as reading, reflecting and engaging with others’ contributions – is de-prioritized. What looks like productivity often masks intellectual exhaustion built on a demoralizing, narrowing scientific vision.

A table of profit margins across industries. The section of text related to this table is below: 1. The four-fold drain 1.1 Money Currently, academic publishing is dominated by profit-oriented, multinational companies for whom scientific knowledge is a commodity to be sold back to the academic community who created it. The dominant four are Elsevier, Springer Nature, Wiley and Taylor & Francis, which collectively generated over US$7.1 billion in revenue from journal publishing in 2024 alone, and over US$12 billion in profits between 2019 and 2024 (Table 1A). Their profit margins have always been over 30% in the last five years, and for the largest publisher (Elsevier) always over 37%. Against many comparators, across many sectors, scientific publishing is one of the most consistently profitable industries (Table S1). These financial arrangements make a substantial difference to science budgets. In 2024, 46% of Elsevier revenues and 53% of Taylor & Francis revenues were generated in North America, meaning that North American researchers were charged over US$2.27 billion by just two for-profit publishers. The Canadian research councils and the US National Science Foundation were allocated US$9.3 billion in that year.

The costs of inaction are plain: wasted public funds, lost researcher time, compromised scientific integrity and eroded public trust. Today, the system rewards commercial publishers first, and science second. Without bold action from the funders we risk continuing to pour resources into a system that prioritizes profit over the advancement of scientific knowledge.

We wrote the Strain on scientific publishing to highlight the problems of time & trust. With a fantastic group of co-authors, we present The Drain of Scientific Publishing:

a 🧵 1/n

Drain: arxiv.org/abs/2511.04820
Strain: direct.mit.edu/qss/article/...
Oligopoly: direct.mit.edu/qss/article/...

Reduced penetrance of COL1A1/2 pathogenic variants linked with osteogenesis imperfecta: analysis of a large population cohort Osteogenesis imperfecta (OI) is under consideration for inclusion in several genomic newborn screening initiatives, but its penetrance in clinically-unselected populations is currently unknown. It is ...

New pre-print on population penetrance - the first of a set exploring specific gene-disease pairs under consideration for genomic newborn screening. Spoiler alert: careful curation is essential, but penetrance is lower in population than clinical cohorts. www.medrxiv.org/content/10.1...

Huntington's disease successfully treated for first time One of the most devastating diseases finally has a treatment that can slow its progression and transform lives, tearful doctors tell BBC.

www.bbc.co.uk/news/article....

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 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

A Day of Discussion: The ELSI Conference 2025 Authors: Emily Clarke, Tara Clancy, Amy Hunter, Faye Johnson, Simon Jones, Sinduja Manohar, Gracie Mellalieu, Yvette Mellalieu, Melissa McKie, Arti Patel, Peter Style, Shelley Wagon, Sarah Wynn Introd...

Article summarising the the key themes identified at the ELSI Conference which look place earlier this year. Highlighting a range of different priorities and challenges of rare condition clinical trials.

Our new study characterises ELFN1 deficiency as a novel autosomal recessive neurodevelopmental disorder marked by epilepsy, GDD/ID, & movement disorders. Biallelic ELFN1 variants disrupt synaptic protein trafficking to the cell surface—validated through functional assays and mouse/zebrafish models.

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

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

New research set to uncover lost ancient medical texts A team of researchers at the University of Manchester have secured a major €2.5 million (£2.1 million) grant from the European Research Council to uncover lost medical writings that could transform ou...

New research set to uncover lost ancient medical texts

A team of researchers at @manchester.ac.uk have secured a major €2.5 million grant from the @erc.europa.eu to uncover lost medical writings that could transform our understanding of ancient medicine. ⤵️
www.manchester.ac.uk/about/news/n...

OpenSAFELY Schools A collaboration between the National Institute of Teaching and the Bennett Institute for Applied Data Science

"Have you thought about applying the @opensafely model, for data privacy and efficiency, to non-health data?"

YES WE HAVE

Behold the new... OpenSAFELY-Schools!!

schools.opensafely.org

Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes - Nature Genetics Genomic analyses focused on regions that form R-loops identify rare mutations in RNU2-2 and RNU5B-1 in individuals with neurodevelopmental disorders.

New research investigates de novo variants in R-loop forming regions across large-scale genomic datasets identifying RNU2-2 and RNU5B-1 as novel #NDDs genes. Together with RNU4-2, these explain a high number of previously unsolved NDDs cases.
#snRNAs

www.nature.com/articles/s41...

Great talk by Jamie Ellingford about UPD as a cause of rare conditions in the 100k Genomes at the ACGS meeting in Birmingham

Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity Genes and Health (G&H) is a biomedical study of adult British-Pakistani and -Bangladeshi research volunteers enriched for autozygosity. We performed whole exome sequencing in 44,028 G&H participants, ...

Great work published today as preprint on 44k exonerated from the Genes and Health study

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

Check out this article by @carolineleacarnall.bsky.social and other members of our Spin Lab team! Funded by @nihr.bsky.social MH-TRC Mission, hosted at @oxhealthbrc.bsky.social: www.sciencedirect.com/science/arti...