RNU4-2RNA, U4 small nuclear 2
Autism Reports / Total Reports
0 / 12Rare Variants / Common Variants
54 / 0Aliases
-Associated Syndromes
ReNU syndrome, DD, ID, ReNU syndrome, DD, ID, epilepsy/seizures, ReNU syndromeChromosome Band
12q24.23Associated Disorders
-Relevance to Autism
Greene et al., 2024 performed a genetic association analysis comparing the burden of rare variants in 41,132 noncoding genes between 5,529 unrelated cases with intellectual disability and 46,401 unrelated controls and identified RNU4-2 as the most strongly associated gene with de novo variants among 47 cases in two regions of RNU4-2 (n.6270 and n.7379) in the etiology of a syndrome characterized by intellectual disability, microcephaly, short stature, hypotonia, seizures and motor delay; n.64_65insT was the most common RNU4-2 variant and was observed as a de novo mutation in 33 different families. Chen et al., 2024 subsequently identified an 18 bp region of RNU4-2 that was severely depleted of variation in the general population but in which heterozygous variants in 115 individuals with neurodevelopmental disorders were identified; most of these individuals (77.4%) had the same highly current single base insertion (n.64_65insT), and in 54 individuals where it could be determined, de novo variants were all on the maternal allele. Furthermore, characterization of detailed phenotypic information for a subset of 49 individuals (42 with the n.64_65insT variant) in this report demonstrated that RNU4-2 was responsible for a neurodevelopmental syndrome characterized by global developmental delay, intellectual disability, dysmorphic features, short stature, microcephaly, hypotonia, seizures, structural brain abnormalities detected by brain MRI, and behavioral abnormalities, including autism spectrum disorder in 21/44 individuals (48%). Lastly, RNA-seq analysis of blood from five individuals with RNU4-2 variants, including three with the n.64_65insT variant, in Chen et al., 2024 demonstrated an increased use of unannotated 5 splice sites (mean 8.8 events in individuals with RNU4-2 variants compared with 0.7 in both 378 unmatched controls and ten controls matched on genetic ancestry, sex and age at consent; Wilcoxon P=4.0105 and P=5.7103, respectively). Investigation of de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and additional cases gathered through international collaborations in Nava et al., 2025 resulted in the identification of 145 previously unreported probands with (likely) pathogenic variants in RNU4-2; assessment of clinical data available for 143 of these patients revealed that while all patients presented with neurodevelopmental delay with variable degrees of intellectual disability, most variants located in the T-loop and RBM42 interacting region (including the recurrent n.64_65insT variant) resulted in a more severe phenotype, whereas variants in the stem III region resulted in a milder phenotype. RNA-seq on lymphocyte cultures from 19 individuals with RNU4-2 variants in this report not only confirmed the alternative 5 splice site abnormalities previously reported in Chen et al., 2024 but also demonstrated that severe phenotypes associated with variants n.64_65insT, n.67A>G, n.68A>C and n.70T>C formed a distinct cluster, while milder phenotypes associated with n.72_73del, n.75C>G and n.76C>T appeared intermediate between severe cases and controls. Lastly, Nava et al., 2025 identified a specific RNU4-2 episignature, the strength of which correlated with disease severity and variant location.
Molecular Function
RNU4-2 encodes the U4 small nuclear RNA (snRNA) component of the small nuclear ribonuculeoprotein (snRNP) U4, which is one of the five snRNPs of the major spliceosome.
SFARI Genomic Platforms
Reports related to RNU4-2 (12 Reports)
# | Type | Title | Author, Year | Autism Report | Associated Disorders |
---|---|---|---|---|---|
1 | Recent recommendation | - | Daniel Greene et al. (2024) | No | Epilepsy/seizures |
2 | Support | - | Rachel Schot et al. (2024) | No | - |
3 | Primary | - | Yuyang Chen et al. (2024) | No | ASD, epilepsy/seizures |
4 | Support | - | Irene Valenzuela et al. (2024) | No | Autistic behavior, epilepsy/seizures, stereotypy |
5 | Support | - | Kristen Barbour et al. (2024) | No | ASD, ID, stereotypy |
6 | Support | - | Jessica Rosenblum et al. (2025) | No | ASD or autistic features, epilepsy/seizures |
7 | Support | - | Steven Laurie et al. (2025) | No | ASD |
8 | Support | - | Shloka Negi et al. (2025) | No | - |
9 | Support | - | Alessandro Bruselles et al. () | No | ASD, epilepsy/seizures |
10 | Recent Recommendation | - | Caroline Nava et al. (2025) | No | ASD, stereotypy, epilepsy/seizures |
11 | Support | - | Yukiko Kuroda et al. () | No | ASD |
12 | Support | - | Aida M Bertoli-Avella et al. () | No | - |
Rare Variants (54)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
n.66A>G | - | non_coding_transcript_variant | De novo | - | - | 40413032 | Yukiko Kuroda et al. () | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | - | 40413032 | Yukiko Kuroda et al. () | |
n.77_78insC | - | non_coding_transcript_variant | De novo | - | - | 40413032 | Yukiko Kuroda et al. () | |
n.62T>C | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.63T>C | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.64dup | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.65A>G | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.66A>G | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.67A>G | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.67A>G | - | non_coding_transcript_variant | Unknown | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.68A>C | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.69C>T | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.70T>C | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.75C>G | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.76C>T | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.76C>T | - | non_coding_transcript_variant | Unknown | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.76del | - | non_coding_transcript_variant | Unknown | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.78A>C | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.92C>G | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.111C>T | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | - | 38991538 | Yuyang Chen et al. (2024) | |
n.77_78insT | - | non_coding_transcript_variant | De novo | - | - | 38991538 | Yuyang Chen et al. (2024) | |
n.72_73del | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.45_46insT | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.64_65insT | - | non_coding_transcript_variant | Unknown | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.65_66insT | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.76_77insT | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.77_78insG | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.77_78insT | - | non_coding_transcript_variant | De novo | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.77_78insT | - | non_coding_transcript_variant | Unknown | - | - | 40379786 | Caroline Nava et al. (2025) | |
n.69C>T | - | non_coding_transcript_variant | De novo | - | - | 39369315 | Irene Valenzuela et al. (2024) | |
n.64_65insT | - | non_coding_transcript_variant | Unknown | - | - | 39825153 | Steven Laurie et al. (2025) | |
n.64dup | - | non_coding_transcript_variant | De novo | - | Simplex | 38991538 | Yuyang Chen et al. (2024) | |
n.65A>G | - | non_coding_transcript_variant | De novo | - | Simplex | 38991538 | Yuyang Chen et al. (2024) | |
n.68dup | - | non_coding_transcript_variant | De novo | - | Simplex | 38991538 | Yuyang Chen et al. (2024) | |
n.69C>T | - | non_coding_transcript_variant | De novo | - | Simplex | 38991538 | Yuyang Chen et al. (2024) | |
n.76C>T | - | non_coding_transcript_variant | De novo | - | Simplex | 38991538 | Yuyang Chen et al. (2024) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | - | 39423747 | Kristen Barbour et al. (2024) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | - | 39369315 | Irene Valenzuela et al. (2024) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | - | 39434505 | Jessica Rosenblum et al. (2025) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | Simplex | 38991538 | Yuyang Chen et al. (2024) | |
n.64_65insT | - | non_coding_transcript_variant | Unknown | - | Simplex | 38991538 | Yuyang Chen et al. (2024) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | Unknown | 38991538 | Yuyang Chen et al. (2024) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | Simplex | 39862869 | Shloka Negi et al. (2025) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | Simplex | 38859706 | Rachel Schot et al. (2024) | |
n.72_73del | - | non_coding_transcript_variant | Familial | Paternal | - | 40379786 | Caroline Nava et al. (2025) | |
n.70T>C | - | non_coding_transcript_variant | De novo | - | Simplex | 39434505 | Jessica Rosenblum et al. (2025) | |
n.64_65insT | - | non_coding_transcript_variant | Unknown | - | Multiplex | 40379786 | Caroline Nava et al. (2025) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | Simplex | 39369315 | Irene Valenzuela et al. (2024) | |
n.64_65insT | - | non_coding_transcript_variant | De novo | - | Simplex | 40011755 | Alessandro Bruselles et al. () | |
n.64_65insT | - | non_coding_transcript_variant | Unknown | Not maternal | Simplex | 38991538 | Yuyang Chen et al. (2024) | |
n.30A>T | - | non_coding_transcript_variant | Familial | Maternal | Multiplex | 40011755 | Alessandro Bruselles et al. () | |
n.43_44insT | - | non_coding_transcript_variant | Familial | Maternal | Simplex | 40011755 | Alessandro Bruselles et al. () |
Common Variants
No common variants reported.
SFARI Gene score
High Confidence, Syndromic


Score Delta: Score remained at 1S
criteria met
See SFARI Gene'scoring criteriaWe considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."
10/1/2024

Increased from to 1S
Krishnan Probability Score
Score 0.44333900998265
Ranking 16755/25841 scored genes
[Show Scoring Methodology]