Patients with rare disorders often face long diagnostic odysseys even after comprehensive evaluation of variants in protein-coding regions. We set out to determine how often undiagnosed patients have disease-causing variants outside of these regions.

Using the Genomics England 100k genomes project data we systematically identified de novo variants that likely disrupt regulatory processes, in Promoters, UTRs and UTR introns , in 8,040 individuals

We identified eleven de novo variants, plus an additional variant that overlapped the position of one of the initial eleven. After clinical review, 10 were thought to be likely diagnostic, 6 of which are confirmed diagnoses.

We next explored the burden that these variants may represent in rare disease. While we did see an appreciable increase in variants with the potential to disrupt regulation in cases vs controls, the difference wasn't statistically significant for any particular region/annotation

🗝️Key conclusion - Promoter and UTR variants likely to disrupt regulation represent a modest but appreciable contribution to rare disease, and should be incorporated into diagnostic pipelines.

I would like to give a very heartfelt thanks to everyone who has contributed to this work over the last three years, in particular @DrABlakes , @DrJennyLord , Scott Findlay, @smbanka and @nickywhiffin , who have worked very hard to get this out!

Finally, this would not have been possible without the support of all the participants and families enrolled in the 100k genomes project, their recruiting clinical teams, and the staff at Genomics England, to whom we are eternally grateful.

@Alextremophile Congrats :)

@chris_wigley Thank you! I’m very happy excited to be sharing some of the findings with you all at the research summit in the 19th!

@Alextremophile Very nice ! Congrats !:)

@Evol_Molly Thank you!! I’m super excited about it 😍

@Alextremophile Nice! For SNPs, are there resources for either 1) TF binding prediction difference between alleles of a SNP (eg, genome wide, such as UCSC JASPAR track but for difference between alleles); or 2) server that outputs the difference between two SNP alleles of a query sequence?

@CarlosEAlvare17 Hey Carlos, this is a great question. Have you checked out the tool we used here- FABIAN? I don’t think it directly compares but it would output scores that you could work with to compare yourself?

@Alextremophile Fantastic news and really interesting area!

@Alextremophile @SofiaDouzgou Would love to read this article.