This week on The Genetics Podcast, Patrick is joined by Dr. Nicky Whiffin, Associate Professor and Wellcome Career Development Fellow at the Big Data Institute, University of Oxford. They discuss the discovery of a new neurodevelopmental syndrome caused by mutations in the small nuclear RNA gene RNU4-2, what this reveals about the non-coding genome and the spliceosome, and how large-scale genome sequencing is reshaping diagnosis, variant interpretation, and the future of genetic medicine.

Show Notes: 

0:00 Intro to The Genetics Podcast

00:59 Welcome to Nicky

02:09 Overview of the non-coding genome and its functional elements

03:59 How small nuclear RNAs drive splicing and exon recognition

04:54 Overview of the major and minor spliceosomes and the role of small nuclear RNAs in intron removal

06:34 Discovery of recurrent de novo RNU4-2 mutations in developmental disorders through large-scale genomics data

12:18 Growth of patient advocacy groups and global networks following the discovery of ReNU syndrome

14:43 Potential for antisense oligonucleotide therapies for ReNU syndrome

16:06 Clinical endpoints, treatment timing, and biomarker development for ReNU

18:32 Impact of RNU4-2 discovery on exome design, genome sequencing adoption, and targeted testing strategies

19:52 Distinct dominant, recessive, and retinal phenotypes arising from variants within RNU4-2

22:15 Open questions on mutation rates and selection in spliceosomal small nuclear RNAs

25:25  Limits of non-coding variant discovery and the unresolved genetic burden in developmental disorders

29:52 Therapeutic upregulation strategies targeting untranslated regions in haploinsufficiency 

33:40 The MRC Centre of Research Excellence in Therapeutic Genomics’ approach to scalable genetic medicines

35:54 Long-term prospects and delivery challenges for gene editing approaches 

36:56 Newborn genome screening, actionability debates, and implications for rare disease diagnosis

40:25 Population genomics insights from unascertained newborn genome sequencing cohorts

42:04 Closing remarks

Find out more: ReNU discovery paper