Intellectual disability
Gene: BRSK1

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

2 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Intellectual disability without seizures was reported in at least three unrelated families with monoallelic BRSK1 variants. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Created: 30 Sep 2026, 7:45 p.m. | Last Modified: 30 Sep 2026, 7:45 p.m.

Panel Version: 11.35

PMID:42805187 (2026) reported 10 individuals from seven families with heterozygous BRSK1 variants and neurodevelopmental disorder; only two individuals had epilepsy. Seizure was either absent or not reported in eight individuals from five unrelated families. These include three families with predicted loss-of-function variants, three independently arising de novo variants, and a de novo p.Gln428Ter variant segregating from an affected father to three affected children with variable developmental delay/intellectual disability. The father and two sons with p.Gln428Ter variant displayed severe developmental delay/intellectual disability and microcephaly, whereas the daughter was only mildly affected suggesting incomplete penetrance for this variant.

Two seizure-free missense variants showed partial loss of function in Drosophila rescue assays. Human reference BRSK1 rescued neuronal, behavioural and synaptic phenotypes caused by loss of the fly orthologue. Together with the independent Zhang et al. cohort (PMID:41035394, 2025) and heterozygous mouse model, the data support monoallelic BRSK1 loss of function as a cause of a variably expressive neurodevelopmental disorder. Developmental delay/intellectual disability can occur in the absence of epilepsy; therefore, the previous concern that cognitive impairment is secondary to early-onset seizures is no longer supported.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype (last accessed 30 September 2026), but associated with green rating on the intellectual disability panel in PanelApp Australia.
Created: 30 Sep 2026, 7:35 p.m. | Last Modified: 2 Oct 2026, 4:32 p.m.

Panel Version: 11.36

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
neurodevelopmental disorder, MONDO:0700092

Publications

42805187

Created: 30 Sep 2026, 7:35 p.m.
Last Modified: 2 Oct 2026, 4:32 p.m.
Panel version: 11.31

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, NOT imprinted

Sources

Expert Review Amber
Literature

Phenotypes

neurodevelopmental disorder, MONDO:0700092

Tags

gene-checked Q3_26_promote_green

OMIM

609235

Clinvar variants

Variants in BRSK1

Penetrance

None

Publications

Panels with this gene