Early onset or syndromic epilepsy

Gene: BRSK1

Green List (high evidence)

Sufficient families and functional work undertaken by Zhang et al (2025), which supports this variant be associated with epilepsy and global dev delay. Seizures appear to start within childhood (often within the first year). Generalized tonic–clonic seizure appear to be common.

Created: 14 Jan 2026, 10:13 a.m. | Last Modified: 14 Jan 2026, 10:13 a.m.

Panel Version: 8.93

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy; global developmental delay

Publications

• 41035394

Green List (high evidence)

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated cases with early onset epilepsy and supportive data from functional and animal model studies (PMID: 41035394)

Created: 23 Oct 2025, 3 p.m. | Last Modified: 23 Oct 2025, 3 p.m.

Panel Version: 8.59

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