RNU4-2

Inheritance Pattern: AD

Disease ID:MONDO:0019118

Submitter: ClinGen

The *RNU4-2* gene was first reported in relation to human disease in two 2024 publications reporting patients with a multi-system neurodevelopmental disorder referred to as ReNU syndrome (PMID: 38821540, PMID: 38991538). Affected patients harbored variants in the heterozygous state, predominantly as *de novo* occurrences on the maternally inherited allele. Clinical features included global developmental delay, intellectual disability, expressive language deficits, hypotonia, facial dysmorphism, short stature, and/or abnormalities in brain morphology such as ventriculomegaly. Visual dysfunction was also reported in the majority of patients, accompanied by features such as strabismus, nystagmus, and/or optic nerve hypoplasia (PMID: 38991538). The disease spectrum associated with *RNU4-2* variants subsequently expanded to include later-onset cases described as non-syndromic retinitis pigmentosa (PMID: 41513982). These cases were distinguishable based on their later ages of onset, germline inheritance on either paternal or maternal alleles within families with multiple affected members, and association with variants located in the vicinity of stem-I, stem-II, and the U4 5′ stem-loop rather than in Stem III or the adjacent T-loop associated with ReNU syndrome. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, cases diagnosed as non-syndromic retinitis pigmentosa vs. ReNU syndrome are similar in their autosomal dominant patterns of inheritance, but differ in molecular mechanism (predominantly inherited variants extending the 5’ internal loop vs. *de novo* variants in the stem-III or the adjacent T-loop region). They also appear to be distinguishable in their clinical features (isolated retinal phenotypes vs. syndromic features affected multiple systems). Therefore, cases caused by monoallelic variants in *RNU4-2* have been split into two separate disease entities. The present curation has focused on the isolated retinal phenotype, referred to as *RNU4-2*-related retinopathy, while the Syndromic Disorders GCEP has separately evaluated *RNU4-2* in relation to neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language (MONDO:0971172). Two suspected disease-causing variants were scored as part of this curation (one base pair substitution and one single-base pair insertion). Together, these variants have been reported in fifteen total probands in one publication (PMID: 41513982). Future functional studies will be required to determine their mechanism of pathogenicity, however, both variants are predicted to alter an internal loop within *RNU4-2* that may impact the stability of the U4/U6 duplex within the spliceosome. At least one patient harbored the variant as a *de novo* occurrence, indicating the tendency of the same variant to recur in multiple unrelated but similarly affected individuals. Four families with co-segregation of the variant with affected status contributed to the scoring of the gene-disease relationship (PMID: 41513982). This gene-disease association is also supported by biochemical evidence that the *RNU4-2* gene produces a non-coding RNA component (U4) of the U2-dependent spliceosome. Some of the genes that produce the U6 RNA component of the spliceosome (*RNU6-1*, *RNU6-2*, *RNU6-8* and *RNU6-9*) similarly harbor variants reported in relation to retinitis pigmentosa (PMID: 41513982). The U4 and U6 components base-pair together in the context of the spliceosome (PMID: 28781166). *RNU4-2* is highly expressed in a subset of ocular tissues from the retina, retinal pigment epithelium, cornea, conjunctiva, and optic nerve (PMID: 30239781). In summary, *RNU4-2* has a Strong association with *RNU4-2*-related retinopathy. Additional evidence from the research and diagnostic settings will be needed to meet the requirement for replication over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on October 1st, 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: Broad Center for Mendelian Genomics

Inheritance Pattern: AD

Disease ID:MONDO:0971172

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0971172

Submitter: ClinGen

The *RNU4-2* gene is located on chromosome 12 at 12q24.23 and encodes the U4 small nuclear RNA, a component of the U4/U6.U5 tri-snRNP complex of the major spliceosome that mediates RNA splicing. The U4/U6 snRNA duplex is important for correctly positioning the U6 ACAGAGA sequence to receive the 5’ splice site during spliceosome activation. *RNU4-2* was first reported in relation to autosomal dominant *RNU4-2*-related ReNU syndrome in 2024 (Chen et al., 2024 PMID: 38991538 and Greene et al., 2024 PMID: 38821540). This multi-system disorder is characterized by moderate to severe global developmental delay/intellectual disability, speech anomalies (mostly non-verbal), hypotonia, abnormal brain MRI (reduced white matter volume, hypoplasia of the corpus callosum, ventriculomegaly, and delayed myelination), dysmorphic facial features, short stature, microcephaly, behavioral issues, seizures and feeding difficulties, as well as variable vision, gastrointestinal, endocrine, skeletal, genitourinary, cardiac, and cutaneous anomalies. Evidence supporting this gene-disease relationship includes case-level data and experimental evidence. Twenty-one unique pathogenic/likely pathogenic variants (12 single nucleotide variants, 9 single base-pair deletion/insertion variants) have been reported in over 200 unrelated probands across two publications (PMID: 38991538, Nava et al., 2025 PMID: 40379786) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The gene disease association is supported by high expression of *RNU4-2* in the developing human brain (PMID: 38991538). Functional studies of RNA-sequencing data from individuals with *RNU4-2*-related ReNU syndrome are consistent with systematic disruption of 5′ splice-site usage (PMID: 38991538, PMID: 40379786). In summary, there is strong evidence to support this gene-disease relationship. No convincing contradictory evidence has emerged to date. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date September 3rd, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0971172

Submitter: PanelApp Australia