Early onset or syndromic epilepsy

Gene: RNU5B-1

Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621302) and the OMIM record was last accessed on 18 December 2025.

Created: 18 Dec 2025, 10:32 p.m. | Last Modified: 18 Dec 2025, 10:32 p.m.

Panel Version: 8.78

Green List (high evidence)

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple unrelated individuals reported with de novo (several recurrent) variants in the RNU5B-1 gene that lead to splicing disruption. All individuals present with a neurodevelopmental disorder, with seizures reported in 6 unrelated cases which can be an early presenting feature.

Created: 28 Jul 2025, 2:45 p.m. | Last Modified: 28 Jul 2025, 3:20 p.m.

Panel Version: 8.15

At least 19 individuals with de novo and/or recurrent variants in RNU5B-1 and a neurodevelopmental disorder characterised by ID/DD, brain MRI abnormalities, hypotonia, microcephaly or macrocephaly, failure to thrive, and in some cases seizures.

PMID: 40379786 (2025) - 15 unrelated probands with heterozygous variants in RNU5B-1. Clinical data was available for 9 individuals who presented with a neurodevelopmental disorder including severe ID/DD (although one patient had normal cognition but attention difficulties) and brain MRI abnormalities. Other features were variable and include hypotonia, epilepsy, ocular abnormalities, acquired microcephaly or macrocephaly and other variable congenital abnormalities. Variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. Functional studies demonstrate variant-specific splicing abnormalities in patient-derived cells which may underline the clinical variability observed in patients.

PMID: 40442284 (2025) - 9 unrelated individuals with de novo variants in RNU5B-1 and a neurodevelopmental disorder characterised by GDD/ID, macrocephaly, eye abnormalities, seizures, hypotonia and failure to thrive, among other variable features - based on 6 cases where phenotype information was available. Variants were again found in regions critical for splicing.

Both studies investigated participants of the 100KGP and/or NHS GMS (6 in PMID: 40379786 and 5 in PMID: 40442284) so likely refer to the same individuals.
Sources: Literature

Created: 28 Jul 2025, 2:38 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Neurodevelopmental disorder, MONDO:0700092

Publications

• 40379786
• 40442284