Podcast recap: Nicky Whiffin on the discovery of ReNU syndrome and what it unlocks for genetic medicine

The majority of rare disease discovery has been linked to protein coding genes, where changes are easier to interpret and easier to capture in routine testing. The most recent episode of The Genetics Podcast reveals that the next wave of diagnoses may increasingly come from non-coding parts of the genome that have either been dismissed or overlooked.

The conversation with Dr. Nicky Whiffin, Associate Professor and Wellcome Career Development Fellow at the Big Data Institute at the University of Oxford, centers on one such breakthrough. Her group and collaborators identified a single recurrent variant in RNU4-2, a small nuclear RNA gene, as a surprisingly common cause of neurodevelopmental disorder. The discovery has rapidly expanded into a global patient community, multiple distinct disease mechanisms within a 145 base pair locus, and a credible path to antisense treatment that could reach patients as early as 2026.

A map of the non-coding genome and the importance of RNU4-2

Only about 1.5% of the genome directly encodes proteins, but that does not mean the rest is inert. There are:

• Non coding parts within protein coding genes, including untranslated regions (UTRs) and introns
• Regulatory DNA, including promoters and enhancers
• Non-coding RNA genes that are transcribed into RNA including tRNAs, rRNAs, long non coding RNAs, and small nuclear RNAs (snRNAs)

The episode focuses on snRNAs because they are core components of the spliceosome, the machinery that removes introns and joins exons to create mature messenger RNA. If splicing goes wrong at scale, many genes can be affected at once. That global leverage is why a small non-coding gene can lead to a major phenotype.

Small RNAs and the spliceosome

Splicing depends on sequence recognition. The spliceosome needs to identify where introns begin and end, as well as the branchpoint. Nicky explains that snRNAs help the spliceosome recognize these motifs and specify where cutting and joining should occur.

She also distinguishes between the major spliceosome, which processes the vast majority of introns, and the minor spliceosome, which handles a much smaller subset. RNU4-2 is part of the major spliceosome. It also has a minor spliceosome counterpart, RNU4ATAC, which was already known to cause developmental disorders. That parallel enhanced the credibility of the RNU4-2 signal.

From unexpected signal to recurrent syndrome

Nicky and her team were analyzing ribosome profiling data and developing methods to annotate variants in regions not typically classified as protein coding but showing signs of translation. A single base insertion in RNU4-2 was highlighted by that pipeline because it appeared to alter a putative open reading frame.

Within the Genomics England dataset, the team identified multiple unrelated individuals with developmental disorders who carried the same de novo insertion in this small locus. The recurrence of an identical variant across independent cases provided strong evidence that this was not background noise. Further analyses supported RNU4-2 as a new and distinct cause of neurodevelopmental disorder.

Prevalence and genetics of ReNU syndrome

Approximately 70 to 75% of individuals diagnosed with ReNU syndrome carry the same single nucleotide insertion. The variant arises de novo and consistently appears on the maternal allele. The biological mechanism underlying this recurrent mutation remains unclear, but its consistency has allowed rapid case aggregation and syndrome delineation.

Population level estimates suggest that RNU4-2 variants account for roughly 0.4% of developmental delay cases. In large developmental disorder cohorts, only a small number of individual genes reach comparable frequencies. What makes this particularly notable is the size of the locus. The relevant functional region spans about 145 base pairs, yet it explains a measurable proportion of cases, underscoring the clinical impact that highly constrained non-coding elements can have.

Nicky explains that variants in different parts of the 145 base pair sequence appear to drive three distinct disorders, likely via three mechanisms:

• A central region associated with dominant de novo ReNU syndrome
• Other structural regions associated with a recessive neurodevelopmental disorder
• A small number of positions associated with retinitis pigmentosa, an eye phenotype

Community formation and a path toward therapy

Following the genetic discovery, families began to connect internationally and establish advocacy groups, including ReNU Syndrome United in the US, with similar efforts emerging in other countries. These organizations have played a central role in patient identification, registry building, and coordination across research groups. The presence of an engaged and organized community has meaningfully accelerated natural history planning and early therapeutic discussions.

Nicky describes accumulating evidence that a single normal copy of RNU4-2 is sufficient, which supports an allele specific knockdown strategy. Antisense oligonucleotides (ASOs) are well suited to downregulating RNA transcripts, and work is already underway to design and advance candidate ASOs. The combination of a recurrent variant, a defined mechanism, and an RNA based target has created a realistic opportunity to move from gene discovery to first in human treatment within a few years of the initial report, with a potential clinical intervention by early 2026.

Several elements still need to be established to support that transition. Robust natural history data are required to define progression, variability, and optimal timing of intervention. There is also active work to develop molecular biomarkers, including reproducible splicing signatures, that could serve as early readouts of treatment effect. Together, these efforts reflect how quickly the field can move when genomic discovery, mechanistic clarity, and community organization align.

Genetic testing implications

The discovery also exposes a structural issue in how patients are tested. Whole genome sequencing captures this region naturally, which is part of why Genomics England was able to contribute so quickly. Exome-first approaches generally miss it.

Nicky describes practical workarounds now being used, including adding targeted probes to exome capture and even running simple PCR screens across unsolved cohorts. The fact that a 145 base pair region can explain a meaningful fraction of cases makes a strong argument for systematically incorporating key non-coding loci into clinical pipelines, even before whole genome sequencing becomes universal.

What this discovery signals for the field

The RNU4-2 story compresses multiple trends into a single case study:

• Whole genome sequencing is not just incremental, it changes what classes of diagnoses are possible
• Mechanism first thinking is what turns discovery into therapy
• Patient communities can rapidly accelerate research readiness
• RNA targeted therapeutics make it plausible to move from gene to treatment in a timeframe that would have been unthinkable a decade ago

Listen to the full episode below.