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Intellectual disability

Gene: BRSK2

Green List (high evidence)

BRSK2 (BR serine/threonine kinase 2)
EnsemblGeneIds (GRCh38): ENSG00000174672
EnsemblGeneIds (GRCh37): ENSG00000174672
OMIM: 609236, Gene2Phenotype
BRSK2 is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: Expert review by Konstantinos Varvagiannis on BRSK2. Hiatt et al. (PMID:30879638) reports on 9 individuals, each with private heterozygous BRSK2 variant. ID features in (8/9). Individuals are not related and all have unique variants as they were identified using "GeneMatcher" tool. Therefore sufficient evidence to classify BRSK2 as Green.
BRSK2 is not associated with any phenotype in OMIM, nor in G2P.
Created: 15 May 2019, 2:04 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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
Created: 16 Mar 2019, 7:45 p.m.

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

Phenotypes
Global developmental delay; Intellectual disability; Autism; Behavioral abnormality

Publications

  • https://doi.org/10.1016/j.ajhg.2019.02.002

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review
  • Expert Review Green
  • Expert Review
Phenotypes
  • Global developmental delay
  • Autism
  • Behavioral abnormality
  • Global developmental delay, Intellectual disability, Autism, Behavioral abnormality
  • Intellectual disability
OMIM
609236
Clinvar variants
Variants in BRSK2
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to BRSK2. Source Expert Review was added to BRSK2. Added phenotypes Global developmental delay, Intellectual disability, Autism, Behavioral abnormality for gene: BRSK2 Publications for gene BRSK2 were changed from https://doi.org/10.1016/j.ajhg.2019.02.002 to 15705853; 23715323; 30879638; 25363768; 28135719 Rating Changed from No List (delete) to Green List (high evidence)

16 Mar 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

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