Intellectual disability
Gene: BRSK1

BRSK1 (BR serine/threonine kinase 1)
EnsemblGeneIds (GRCh38): ENSG00000160469
EnsemblGeneIds (GRCh37): ENSG00000160469
OMIM: 609235, Gene2Phenotype
BRSK1 is in 2 panels

1 review

Arina Puzriakova (Genomics England Curator)

I don't know

Comment on list classification: Rating Amber on the ID panel, as evidence from 7 unrelated cases reported in PMID:41035394 indicates that developmental and cognitive impairment is not a universal feature and these deficits are likely secondary to early-onset seizures, which represent the most prominent manifestation associated with this gene. This is further supported by a case with later onset epilepsy (6 yrs), where no developmental deficits were observed before (or after) seizures.
Created: 23 Oct 2025, 2:57 p.m. | Last Modified: 24 Oct 2025, 9:46 a.m.

Panel Version: 9.149

Zhang et al. 2025 (PMID: 41035394) describe 7 unrelated individuals, born to non-consanguineous Chinese parents, with unexplained epilepsy and heterozygous variants in the BRSK1 gene identified by trio WES. Variants include four SNVs and two indels (2 frameshift, 1 nonsense, 3 missense) - five were de novo, one inherited from an affected parent and one recurrent. No other pathogenic variants in epilepsy genes were identified. BRSK1 is intolerant to LoF variants (pLI = 1 in gnomAD v4.1.0).

Clinical features in affected individuals include epilepsy (7/7) with age of onset before age 1 (with exception of 1 case with age of onset at 6 yrs), variable brain MRI abnormalities (3/7), developmental delay (2 GDD, 1 mental delay, 1 motor delay, 2 without DD). One individual also had ASD and ADHD.

Frameshift and nonsense variants led to complete loss of BRSK1 protein, while one missense variant reduced protein levels. Proteomic analyses demonstrated axonal and synaptic dysfunction. Brsk1 exon 4-7 knockout mice (heterozygous and homozygous) exhibited seizures, neuronal hyperexcitability and neurobehavioral impairments which recapitulated clinical features observed in humans.
Sources: Literature
Created: 23 Oct 2025, 2:47 p.m.

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

Phenotypes
Neurodevelopmental disorder, MONDO:0700092

Publications

41035394

Created: 23 Oct 2025, 2:47 p.m.
Last Modified: 24 Oct 2025, 9:46 a.m.
Panel version: 9.148

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Amber
Literature

Phenotypes

Neurodevelopmental disorder, MONDO:0700092

OMIM

609235

Clinvar variants

Variants in BRSK1

Penetrance

None

Publications

41035394

Panels with this gene

History Filter Activity

23 Oct 2025, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: brsk1 has been classified as Amber List (Moderate Evidence).

23 Oct 2025, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Arina Puzriakova (Genomics England Curator)

gene: BRSK1 was added gene: BRSK1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: BRSK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: BRSK1 were set to 41035394 Phenotypes for gene: BRSK1 were set to Neurodevelopmental disorder, MONDO:0700092 Review for gene: BRSK1 was set to AMBER

Intellectual disability Gene: BRSK1