This work was done as part of a collaboration between Stanford and the Broad and facilitated through the UDN and
@gregor-research.bsky.social consortia. A special thanks to my co-first author Rodrigo Mendez, who identified the RNU6ATAC variants, and @vijayganesh.bsky.social, who led this project!

The spliceosome is large, with many components related to disease, leaving the question… how many more patients can we diagnose (and diseases can we uncover!) by examining the transcriptome for global outlier patterns?

These results demonstrate that examining RNA-sequencing data for transcriptome-wide signatures can increase the diagnostic yield of individuals with rare diseases, provide variant-to-function interpretation of spliceopathies, and uncover novel disease-gene associations.

We also identified an individual with excess minor intron retention events who had rare, highly conserved, compound heterozygous variants in RNU6ATAC that may disrupt the formation of the catalytic spliceosome, suggesting a novel gene-disease candidate!

By examining the RNA-seq data of 390 individuals in a rare disease cohort for patterns of minor intron retention events, we were able to identify four individuals with RNU4atac-opathies, a difficult-to-diagnose disease, caused by biallelic variants in RNU4ATAC (as well as reclassify four variants!).

Spliceopathies are a group of rare diseases that interfere with the function of the spliceosome. Variants in the minor spliceosome snRNA RNU4ATAC have been associated with the retention of a special type of intron called “minor introns”.

Aww thank you! I couldn't have done it without you!