RNU12

Inheritance Pattern: AR

Disease ID:MONDO:1060223

Submitter: ClinGen

The *RNU12* gene is located on chromosome 22 at 22q13.2 and encodes a snRNA (U12), part of the U12-dependent minor spliceosome complex involved in recognition and splicing of minor introns. *RNU12* was first reported in relation to autosomal recessive *RNU12*-related minor spliceopathy disorder in 2017 (Elsaid et al., PMID: 27863452). The features associated with *RNU12*-related disorder are highly variable. Compound heterozygotes with the n.*3C>T variant and a second rare variant in *RNU12* have been described with multiple malformations including clavicular hypoplasia, craniosynostosis, delayed closure of fontanelles, genitourinary malformations, developmental delay, and skin findings such as porokeratosis (Xing et al., PMID: 34085356). Individuals with biallelic variants that do not include the n.*3C>T variant present with cerebellar atrophy, hypotonia, seizure, and global developmental delay (PMID: 27863452). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity, CDAGS syndrome (OMIM:603116) and spinocerebellar ataxia autosomal recessive 33 (OMIM:620208). Nine variants in a non-protein-coding gene that have been reported in ten probands in two publications (PMID: 34085356, 27863452) are included in this curation. Variants in this gene segregated with disease in thirteen additional family members (PMID: 27863452). RNA sequencing analysis on blood from affected individuals revealed significant retention of minor introns in multiple genes, consistent with a dysfunction of *RNU12*, which is involved in minor intron splicing (PMID: 27863452). This gene-disease relationship is supported by experimental data including biochemical function and protein interaction (PMID: 38484052, 27863452). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. Although the total score is 6.3, the Syndromic Disorders GCEP opted to upgrade the classification from Limited to Moderate due to the number of reported cases at this time, as well as convincing functional evidence of minor intron splice impacts. This classification was approved by the ClinGen Syndromic disease GCEP on the meeting date February 20, 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0011287

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0011287

Submitter: G2P