Neonatal diabetes

Gene: RNU4ATAC

Green List (high evidence)

Comment on list classification: There are 12 unrelated individuals with biallelic RNU4ATAC variants and early-onset diabetes (article not yet peer-reviewed). Hence, this gene will be recommended for promotion to Green on Neonatal diabetes panel once the article is published.

Created: 29 Dec 2025, 5:01 p.m. | Last Modified: 29 Dec 2025, 5:01 p.m.

Panel Version: 5.9

MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.
Around 60% of patients also had microcephaly and developmental delay.

Among the 12 families with biallelic RNU4ATAC variants, the variants reported were: n.13C>T, n.16G>A, n.17G>A, n.36T>G, n.36T>C, n.51G>A, n.46G>A, n.48G>A, n.55G>A (recurrent in 5 individuals), n.60G>A.

RNU4ATAC has been linked to several phenotypes in OMIM: Lowry-Wood syndrome, 226960; Microcephalic osteodysplastic primordial dwarfism, type I, 210710; Roifman syndrome, 616651. All three disease entities have clinical overlap, with most common features being epiphyseal dysplasia with intellectual disability, microcephaly, immunodeficiency, and/or retinal anomalies. OMIM accessed on 29th Dec 2025.

Created: 29 Dec 2025, 4:59 p.m. | Last Modified: 29 Dec 2025, 4:59 p.m.

Panel Version: 5.9

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
RNU4ATAC spectrum disorder, MONDO:0100558

Green List (high evidence)

RNU4ATAC is a non-protein-coding gene and a component of the minor spliceosome, a protein-RNA complex mediating splicing of ~700 genes containing U12/minor-type introns. Johnson et al report RNU4ATAC as a novel disease gene causing monogenic autoimmune diabetes (median onset: 20 weeks) with additional immune dysregulation; whole genome sequencing of 7 unrelated individuals identified homozygous or compound heterozygous variants in RNU4ATAC, all known causes of monogenic diabetes had already been excluded. Sanger sequencing of the RNU4ATAC gene in patients with neonatal diabetes of unknown cause identified a further 5 unrelated individuals with biallelic variants in RNU4ATAC. RNA-seq from 3 unrelated individuals confirmed intron retention in comparison to controls. Multi-omic analysis of patient samples revealed a profound B cell developmental defect. This is the first report of pathogenic variants in non-coding genes causing monogenic diabetes, and also extends the phenotype of RNU4ATACopathies.
Sources: Literature

Created: 11 Dec 2025, 9:23 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neonatal diabetes; developmental delay; microcephaly; skeletal abnormalities; hypothyroidism; humoral immune defect; hepatic disorder; growth failure; failure to thrive; atopic dermatitis

Publications

• MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567

Mode of pathogenicity
Other