Overview · snRNA spliceosome disorders
ReNU syndrome and related snRNA disorders
ReNU syndrome is a neurodevelopmental disorder caused by de novo variants in RNU4-2, which encodes U4 — a 145-nucleotide small nuclear RNA of the major spliceosome, not a protein. It was first reported in 2024, by two groups at once, from genome sequencing in the 100,000 Genomes Project. It went unrecognised for so long because RNU4-2 is non-coding: exome sequencing, the usual first test and the basis of most large studies of intellectual disability, does not capture it, so finding it takes genome sequencing or targeted testing.
It is characterised mainly by intellectual disability, most often severe or profound, with little or no speech; neonatal hypotonia; microcephaly and short stature; autistic features with midline stereotypies reminiscent of Rett syndrome; and epilepsy in about half. Brain MRI is abnormal in about nine in ten (enlarged ventricles, corpus callosum anomalies). Most patients carry the same single-base insertion, n.64_65insT, and where a variant sits predicts severity. Related disorders arise from other spliceosomal snRNA genes, and from different parts of RNU4-2 itself.
How common: 60 of 8,841 people in the 100,000 Genomes Project whose neurodevelopmental disorder standard testing had not explained (0.7%). The often-quoted “0.4% of all NDD” is extrapolated from that referred cohort, assuming 40% had already been diagnosed — not a population prevalence.
The snRNA neurodevelopmental disorders
Same machine, different parts: where the variant sits decides the disorder.
- Inheritance:
- Dominant, almost always de novo (maternal allele)
- Where:
- T-loop (n.62–70) and stem III (n.75–78) of the U4/U6 duplex — the original 18-nt region n.62–79
- Recurrent:
- n.64_65insT (~73–77%), n.76C>T, n.77_78insT
- Hallmarks:
- Moderate–severe DD/ID, microcephaly, hypotonia, short stature, seizures, absent speech
- How common:
- 60 of 8,841 undiagnosed NDD in the 100,000 Genomes Project (0.7%); the quoted 0.4% of all NDD is an extrapolation · Chen 2024; Greene 2024; Nava 2025
- Inheritance:
- Biallelic (homozygous or compound heterozygous)
- Where:
- Outside the ReNU region, in function-critical cores of stem II (n.6–11), the k-turn (n.27–33, n.42–46), the Sm site (n.118–126) and the terminal stem-loop
- Recurrent:
- no single recurrent variant
- Hallmarks:
- Distinct white-matter changes incl. enlarged perivascular spaces; hypotonia 84%, seizures 63%
- How common:
- 38 individuals described · Rius 2026
- Inheritance:
- Dominant de novo, and recessive (biallelic)
- Where:
- 5′ end of U2-2 (nucleotides 4 and 35 for the dominant form)
- Hallmarks:
- Severe, complex epilepsy (all 25 dominant cases first described), microcephaly (7 of 9 discovery cases), hyperventilation
- How common:
- Dominant ~20% as common as ReNU; recessive at least twice the dominant · Greene 2025; Leitão 2026
- Inheritance:
- Dominant, de novo
- Where:
- U5 5′ loop I
- Recurrent:
- n.39C>G, n.44A>G
- Hallmarks:
- Global DD, relative macrocephaly, seizures, failure to thrive
- How common:
- Few individuals so far; RNU5A-1 (also U5) a strong candidate · Jackson 2025; Nava 2025
- Inheritance:
- Dominant, inherited or de novo
- Where:
- Three-way junction of the U4/U6 duplex (RNU4-2 n.18_19insA, n.56T>C) — not the ReNU region
- Recurrent:
- varied
- Hallmarks:
- Non-syndromic progressive retinal degeneration
- How common:
- Up to ~1.4% of undiagnosed RP · Quinodoz 2026
| Disorder | Inheritance | Where the variants sit | Recurrent variants | Hallmarks | How common |
|---|---|---|---|---|---|
ReNU syndrome RNU4-2 | Dominant, almost always de novo (maternal allele) | T-loop (n.62–70) and stem III (n.75–78) of the U4/U6 duplex — the original 18-nt region n.62–79 | n.64_65insT (~73–77%), n.76C>T, n.77_78insT | Moderate–severe DD/ID, microcephaly, hypotonia, short stature, seizures, absent speech | 60 of 8,841 undiagnosed NDD in the 100,000 Genomes Project (0.7%); the quoted 0.4% of all NDD is an extrapolation Chen 2024; Greene 2024; Nava 2025 |
Recessive RNU4-2 NDD RNU4-2 | Biallelic (homozygous or compound heterozygous) | Outside the ReNU region, in function-critical cores of stem II (n.6–11), the k-turn (n.27–33, n.42–46), the Sm site (n.118–126) and the terminal stem-loop | no single recurrent variant | Distinct white-matter changes incl. enlarged perivascular spaces; hypotonia 84%, seizures 63% | 38 individuals described Rius 2026 |
RNU2-2 syndrome RNU2-2 | Dominant de novo, and recessive (biallelic) | 5′ end of U2-2 (nucleotides 4 and 35 for the dominant form) | n.4G>A, n.35A>G | Severe, complex epilepsy (all 25 dominant cases first described), microcephaly (7 of 9 discovery cases), hyperventilation | Dominant ~20% as common as ReNU; recessive at least twice the dominant Greene 2025; Leitão 2026 |
RNU5B-1-related NDD RNU5B-1 | Dominant, de novo | U5 5′ loop I | n.39C>G, n.44A>G | Global DD, relative macrocephaly, seizures, failure to thrive | Few individuals so far; RNU5A-1 (also U5) a strong candidate Jackson 2025; Nava 2025 |
Retinitis pigmentosa RNU4-2, RNU6 | Dominant, inherited or de novo | Three-way junction of the U4/U6 duplex (RNU4-2 n.18_19insA, n.56T>C) — not the ReNU region | varied | Non-syndromic progressive retinal degeneration | Up to ~1.4% of undiagnosed RP Quinodoz 2026 |
The minor spliceosome has its own snRNA disorders: biallelic RNU4ATAC variants cause MOPD1 / Taybi–Linder, Lowry–Wood and Roifman syndromes.
Common features of ReNU syndrome
Individuals with n.64_65insT and clinical data (n ≈ 103), Nava et al. 2025.
GeneReviews adds sleep disturbance, aggressive or self-injurious behaviour, kidney and urinary-tract anomalies, and bone involvement — club feet, hip dysplasia, joint hyperlaxity, osteopenia or low-impact fractures.
How U4 works — and where the variants hit
U4 snRNA paired with U6 in the spliceosome, with the regions behind each disorder.
Scroll sideways to see the whole molecule →
- 1U4 holds U6
In the U4/U6.U5 tri-snRNP, U4 base-pairs with U6 (stems I, II and III) and keeps it inactive.
- 2U4 is unwound away
To activate splicing the U4/U6 duplex is unwound and U4 leaves the spliceosome.
- 3U6 reads the 5′ splice site
Freed U6’s ACAGAGA box pairs with the intron’s 5′ splice site. The T-loop and stem III position it for this.
ReNU variants sit exactly where U6 is positioned, so U6 lands on the wrong place and patients’ cells choose alternative 5′ splice sites. Recessive variants hit the sites that bind U6 (stem II), proteins (the k-turn, the Sm ring) or the terminal stem-loop, and lower how much U4 the cell makes.
Every possible change, measured
521 variants in the transcript · 151 depleted
Saturation genome editing made each change in the cell’s own RNU4-2 and counted how well the cells grew. Lower = the edited U4 supports cells less well.
Scroll sideways →
A lab measure of cell fitness (haploid HAP1 cells), not of patients. All 18 ReNU variants tested were depleted, and lower scores went with more severe ReNU. The assay was calibrated as clinical evidence only inside the critical region; outside it, a depleted score points to a possible recessive effect. The retinitis pigmentosa variant n.56T>C scores normally — a cell-fitness assay does not read a retina-specific effect. On a computer, hover a point for its name and score. Data: De Jonghe et al., Nature 2026, Supplementary Table 1 (CC BY 4.0).
Inside the ReNU critical region
The original 18 nt (n.62–79) by U4/U6 domain, with each recurrent variant; saturation editing narrows the region that matters to n.62–70 and n.75–78.
Counts are probands among 146 with a pathogenic/likely pathogenic RNU4-2 variant; domain boundaries as Nava et al. 2025 (the saturation-editing and Rius papers draw the T-loop as n.63–70 and stem III as n.75–79). The T-loop/quasi-pseudoknot and stem III position the U6 ACAGAGA box for 5′ splice-site recognition.
- T-loop (quasi-pseudoknot) variants — n.64_65insT and its neighbours — give the classic, more severe picture.
- Stem III variants are milder. Everyone with n.76C>T (n = 10) walked (four at a normal age) and spoke (simple sentences or normal language); microcephaly 3/10, short stature 1/10, MRI normal in 6/8, and seizures were fever-sensitive and well controlled. Other stem III variants (n = 9) were similarly mild.
- Other T-loop and RBM42-region variants (n.65A>G, n.66A>G, n.67A>G, n.70T>C) look the same as n.64_65insT.
- Blood RNA shows disrupted 5′ splice-site choice, and the methylation episignature tracks variant location and severity.
- Biallelic variants outside the region (stem II, the k-turn, the Sm site, the terminal stem-loop) cause a different, recessive disorder with reduced U4 levels — not ReNU.
Testing, management and counselling
Testing
RNU4-2 is not included in commercially available clinical exome capture; genome sequencing (or targeted RNU4-2 analysis) is needed. Off-target exome reads occasionally cover the region, so reanalysis can sometimes find it. Prenatal genome testing matters: 60% have prenatal findings.
Management
Supportive and multidisciplinary: development and behaviour, seizures, feeding and GI, kidney/urinary anomalies, bone health and sleep, with regular surveillance. Consider avoiding or limiting medications that affect bone health (e.g. steroids).
Counselling
Almost always de novo, and on the maternal allele where it could be phased. Very rarely inherited from a mildly affected parent; maternal mosaicism has been seen. An affected individual's offspring risk is in principle 50% (it has been hypothesised to be lower when the variant is carried by a male). Prenatal and preimplantation testing are possible once the variant is known.
For families
Patient organisations and plain-language guides. Checked 2026-10-10; the portal is not affiliated with them.
- ReNU Syndrome United ↗
RNU4-2 · US 501(c)(3) nonprofit
Family community and parent group, a community map, a newly-diagnosed checklist, newsletters, an annual conference and research-study listings.
- ReNU2 Foundation ↗
RNU2-2 · dominant and recessive forms
Explains RNU2-2 disorder for families, with a family community, newly-diagnosed guidance, school and caregiver resources, and a guide for clinicians.
- Unique family guide ↗
RNU4-2 · Unique, UK rare chromosome & gene disorder charity
A plain-language guide, “RNU4-2 – ReNU syndrome” (PDF), written for families at the start of the diagnosis.
Sources
Read 2026-10-09. Teaching and decision support — confirm against the current GeneReviews chapter.
- Chen et al. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome. Nature 2024 — PMID 38991538
- Greene et al. Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders. Nat Med 2024 — PMID 38821540
- Nava et al. Dominant variants in major spliceosome U4 and U5 snRNA genes cause NDDs through splicing disruption. Nat Genet 2025 — PMID 40379786
- Barbosa et al. RNU4-2–Related Autosomal Dominant Neurodevelopmental Disorder. GeneReviews — PMID 42190036
- Rius et al. Biallelic variants in RNU4-2 cause a recessive NDD with distinct white matter changes. Nat Genet 2026 — PMID 41951959
- De Jonghe et al. Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders. Nature 2026 — PMID 41951737
- Greene et al. Mutations in the snRNA gene RNU2-2 cause a severe NDD with prominent epilepsy. Nat Genet 2025 — PMID 40210679
- Leitão et al. Frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies. Nat Genet 2026 — PMID 41912934
- Jackson et al. R-loop forming regions identify RNU2-2 and RNU5B-1 as NDD genes. Nat Genet 2025 — PMID 40442284
- Quinodoz et al. Dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa. Nat Genet 2026 — PMID 41513982