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| Intellectual disability v9.149 | BRSK1 | Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset of epilepsy compared to other cases (6 yrs), where no developmental deficits were observed before or after seizures.; to: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.149 | BRSK1 | Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.; to: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset of epilepsy compared to other cases (6 yrs), where no developmental deficits were observed before or after seizures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.149 | BRSK1 | Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appear to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.; to: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.149 | BRSK1 | Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.; to: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appear to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.149 | BRSK1 | Arina Puzriakova Classified gene: BRSK1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.149 | BRSK1 | Arina Puzriakova Added comment: Comment on list classification: Rating Amber on the ID panel as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.149 | BRSK1 | Arina Puzriakova Gene: brsk1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.148 | BRSK1 |
Arina Puzriakova 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 Added comment: 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 |
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| Intellectual disability v2.784 | BRSK2 |
Konstantinos Varvagiannis gene: BRSK2 was added gene: BRSK2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: BRSK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: BRSK2 were set to https://doi.org/10.1016/j.ajhg.2019.02.002 Phenotypes for gene: BRSK2 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality Penetrance for gene: BRSK2 were set to unknown Review for gene: BRSK2 was set to GREEN gene: BRSK2 was marked as current diagnostic Added comment: Hiatt et al. (2019 - https://doi.org/10.1016/j.ajhg.2019.02.002) report on 9 individuals, each with private heterozygous BRSK2 variant. Features included among others speech or motor delay, ID (8/9), ASD and variable behavioral anomalies. 6 variants predicted LoF (stopgain, frameshift or affecting splice-site) while 3 additional ones were missense (2 in the protein kinase domain and 1 in the kinase-associated 1 domain). In 6 individuals the variant had occurred as a de novo event while for 3 others parental samples were unavailable. Given the unknown inheritance, a single variant did not meet sufficient ACMG criteria to be classified as P/LP. All variants had in silico predictions supporting a deleterious effect and were absent from bravo database and gnomAD, where the gene appears to be relatively intolerant to protein-altering variation. As the authors note BRSK2 encodes a serine/threonine protein kinase involved in axonogenesis and polarization of cortical neurons. Although Brsk2- (or Brsk1-) knockout mice appear to be healthy and fertile, double knockouts for these genes resulted in pups with decreased spontaneous movement, poor response to tactile stimulation that died shortly after birth. In mice Brsk2 (and Brsk1) expression is restricted to the nervous system (PMID cited by the authors: 15705853) while in humans this gene is most highly expressed in brain (PMID cited: 23715323 - GTEx project). BRSK2 has been shown to interact with other neurodevelopmental genes eg. TSC2, PTEN, WDR45. Within the cohort of individuals studied, there was statistically significant enrichment for de novo BRSK2 variants when compared to the estimated backround mutation rate. Two further BRSK2 de novo protein-altering variants were previously reported in individuals with neurodevelopmental disorders (Iossifov et al. - PMID: 25363768 and DDD study - PMID: 28135719) although the missense variant in the latter study is also present in gnomAD database. BRSK2 is not associated with any phenotype in OMIM, nor in G2P. The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. among those participating in the study). As a result, this gene can be considered for inclusion in the ID panel as green (or amber). Sources: Literature |
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