🧬 The team from Manchester BRC, @MFTnhs and @FBMH_UoM collaborated with scientists worldwide to analyse the genetic data of thousands of individuals. They studied parts of our genes which have previously been dismissed as ‘dark matter’ or ‘junk DNA’. 🔗 https://t.co/NPg8gpeNdA

@MFTnhs @FBMH_UoM @adam_jackson89 @smbanka @ManchesterBRC @NIHRresearch @swynn_unique @GenomicsEngland @MCRI_for_kids A precise diagnosis for 18-year-old Rose's seizures and developmental delay had proved difficult to find. Thanks to this research, Rose, from Stretford in Manchester, received a diagnosis of one of the newly discovered conditions last year. 👇 https://t.co/5Mwr8MT3qP

🧬 A breakthrough by @MFTnhs and @FBMH_UoM researchers could provide a genetic explanation for thousands of people with neurodevelopmental conditions. This paves the way for improved diagnosis and opens new doors for future treatments. Read more 👇 https://t.co/5Mwr8MT3qP

📰 Two groundbreaking genetic discoveries from Manchester BRC could provide answers for thousands of people with neurodevelopmental conditions globally. Rose from Manchester received a diagnosis of one of the newly discovered conditions after 18 years 👇 https://t.co/NPg8gpeNdA

Special note of thanks and appreciation to @smbanka for overseeing this work and being an incredible supervisor.

This work would not have been possible without the fantastic resources from @GenomicsEngland, @decodegenetics and @Solve_RD

Finally, taking together RNU4-2, RNU2-2 and RNU5B-1, across multiple cohorts, we estimate that over 1% of unsolved NDD may be explained by heterozygous variants in these genes.

We find pathogenic RNU2-2 variants to cluster in the region of the snRNA which interacts with U6 or the pre-mRNA branchpoint whilst RNU5B-1 variants cluster in stem loop I, involved in exon apposition.

Both genes are part of the major splicesome. Splicing is a critical cellular process for making mature mRNA by joining together the coding regions (exons) and excising the non-coding regions. Disruption to normal splicing causes a range of developmental problems.

So how these variants cause human disorders?

Thanks to @j_ellingford for his expertise. And others also not on X.

As the genes are not polyadenylated, we could not use GTeX data reliably. SmallRNA-Seq shows both genes to be highly expressed in the developing human brain & retina. This proves that RNU2-2 (known as RNU2-2P till recently) is unlikely to be a pseudogene.

Thanks to @DrABlakes + all the clinicians and families for their help. Those on X [@MelodyRedman, @JenCampbellKhan, @MeenaBalasubra5, @Norashannon14] and several who are not.

Clinical studies showed that patients with the RNU2-2 disorder have dev del, microcephaly & seizures. Whereas RNU5B-1 disorder causes global developmental delay and a tendency towards macrocephaly.

Thanks to Profs Tiong Tan (@MCRI_for_kids) and Jong Hee Chae (@SeoulNatlUni) for powering this collaboration.

We also find enrichment for RNU2-2 & RNU5B-1, genes without known disease associations Working with teams in Europe, Australia & S. Korea we find many more cases with variants within variation depleted regions of the two genes.

We find distributions of R-loop region de novo variants are distinct in rare disease and controls. In patients most enriched gene types included small non-coding RNAs (snRNAs), which is primarily driven by variants in the ReNU syndrome related RNU4-2 gene.

Thanks to a super MSc student @NishiThake91821 for this work.

In addition to the classical double helix, DNA forms other context-dependant structures such as the DNA-RNA hybrids - R-loops Using data from >15k rare disease or population control trios we find de novo variants to be enriched in R-loops forming regions of the genome.

We are excited to share our new paper out today in Nature Genetics which explores de novo mutations in DNA secondary structure and identifies two novel #diseasegenes https://t.co/sLRcoc0to5