Predicting the impact of rare variants on RNA splicing in CAGI6. New paper from us ⁦CAGI⁩ #CAGI6 thank you ⁦Jenny Lord⁩ ⁦Carolina Jaramillo Oquendo⁩ ⁦Htoo Aung Wai⁩ ⁦Steve Mount⁩ ⁦Predrag Radivojac⁩ link.springer.com/article/10.100…

Excited to share our work on the diagnostic power of genome sequencing when directly assessing cases with exome data - 8% additional yield - if we analyze genomes as more than an exome. Thanks Monica Hsiung Wojcik Rami Abou Jamra Heidi Rehm and Broad CMG GREGoR Consortium collaborators!

Happy to share our latest work where we evaluate the effectiveness of missense variant effect predictors in classifying the disease relevance of variants. This work was done as part of the CAGI6 Annotate-All-Missense challenge. 🧵 biorxiv.org/content/10.110…

Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database biorxiv.org/cgi/content/sh… #biorxiv_genomic

CGM at MGH investigators Anne O'Donnell-Luria, Heidi Rehm, Talkowski Lab with first author Monica Hsiung Wojcik find that genome sequencing has unique capabilities that uplift the diagnosis by 8% for individuals with rare disease and negative exome sequencing. More here: nejm.org/doi/10.1056/NE…

We explored why pathogenic variants are present in the gnomAD database for early-onset, severe, dominant conditions. Explanations identified for most but some likely due to incomplete penetrance though more study needed. 1/3

A lovely piece on the impact of our work by Ian Sample The Guardian including a lovely quote from an RNU4-2 mum: "This where the data meets real life. We like to refer to RNU4-2 as “renew”, as our family is being renewed by this new information and hope for the future.” ❤️

"feeling that like we’ve been on this deserted island for eight years and now all of a sudden, you’re sort of like looking around through the branches of the trees. It’s like, wait a minute, there are other people on this island" ❤️

I very much enjoyed writing this Nature News & Views piece on the RNU4-2 story. Please read on if you want to learn more about how a non-coding variant was discovered to be one of the most frequent causes for developmental diseases. (thx M. Rissom for sketch) nature.com/articles/d4158…

I wrote a blog post to break down the science behind RNU4-2 in a way that families could understand: rarediseasegenomics.org/blog/rnu4-2-th… Key lesson: truly lay writing is incredibly important, but also super hard (this took me a while!) If you have any RNU4-2 families, please do share!

Long reads for rare disease diagnosis; preprint w/ Shloka Negi Jean Monlong + many others. TLDR: Long-read sequencing reveals a lot more of the genome but interpreting the added information requires removing short-read bias from our current knowledge + DBs medrxiv.org/content/10.110…

We’re thrilled to announce the publication of SpliceVarDB: A comprehensive database of experimentally validated human splicing variants in AJHG 🧬 📖 cell.com/ajhg/fulltext/… #splicing #GeneChat

Another splicesomal RNA implicated in recurrent mutations leading to neurodevelopmental disorders, and yet again based on the whole genome sequencing of patients Genomics England who consented for responsible on going research to help understand their (or their child's) disease

Use of PP3/BP4 evidence from calibrated computational prediction tools has little impact on the number of variants classified as Pathogenic or Likely Pathogenic #ACMG/AMP #variantclassification #computational predictors bit.ly/3ZtV0cn

Analysis of R-loop forming regions identifies RNU2-2P and RNU5B-1 as neurodevelopmental disorder genes medrxiv.org/cgi/content/sh… #medRxiv

Thrilled to share a new preprint on the role of RNU4-2 and RNU5B-1 variants in neurodevelopmental disorders, now online in MedRxiv. 1/12 🧵medrxiv.org/content/10.110…

Excited to share our nature paper introducing constraint metrics for #mtDNA! Constraint models are powerful tools that were missing for mtDNA—until now. By applying our model to #gnomAD, we reveal which sites in mtDNA are most crucial for health & disease nature.com/articles/s4158…

See our paper in GIM here. If you publish on variants, PLEASE use variantvalidator.org, or even better, just submit them to ClinVar before article submission (you can request a 6 month embargo), to both validate your variant naming AND make them findable by all!

Excited to report our study in NEJM on the discovery of deletions in a long noncoding RNA gene 🧬 (𝘊𝘏𝘈𝘚𝘌𝘙𝘙) as the cause of a newly defined human neurodevelopmental disorder 🧠. 🧵1/10 nejm.org/doi/full/10.10…