Human Gene Module / Chromosome 12 / RNU4-2

RNU4-2RNA, U4 small nuclear 2

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
0 / 12
Rare Variants / Common Variants
54 / 0
Aliases
-
Associated Syndromes
ReNU syndrome, DD, ID, ReNU syndrome, DD, ID, epilepsy/seizures, ReNU syndrome
Chromosome Band
12q24.23
Associated 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
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

1

High Confidence

See all Category 1 Genes

We 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
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1S

Increased from to 1S

Krishnan Probability Score

Score 0.44333900998265

Ranking 16755/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
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