I am delighted to share with you the news that our shiny new paper has hit the shelves in Genome Medicine!! link.springer.com/article/10.1... Key points (A 🧵):

Individuals with rare conditions often face long diagnostic odysseys, despite advancements in sequencing technologies. We wanted to know if we could find new diagnoses by looking beyond the usual protein-coding candidates, incorporating promoters, and UTRs into a diagnostic framework.

We identified eleven de novo variants with the potential to disrupt regulatory processes, one of which also appeared in an additional participant, but had not been flagged as a de novo variant.

After clinical review, 10 were selected that likely contribute to the participant’s phenotype, 6 of which are confirmed diagnoses. (huge thanks to Alex Blakes, Sid Banka and @drjennylord.bsky.social here! ) link.springer.com/article/10.1...

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...

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!)

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.