Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder

Am J Hum Genet. 2019 Apr 4;104(4):701-708. doi: 10.1016/j.ajhg.2019.02.002. Epub 2019 Mar 14.


Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/threonine-protein kinase BRSK2. All probands have a speech delay, and most present with intellectual disability, motor delay, behavioral issues, and autism. Six of the nine variants are predicted to result in loss of function, and computational modeling predicts that the remaining three missense variants are damaging to BRSK2 structure and function. All nine variants are absent from large variant databases, and BRSK2 is, in general, relatively intolerant to protein-altering variation among humans. In all six probands for whom parents were available, the mutations were found to have arisen de novo. Five of these de novo variants were from cohorts with at least 400 sequenced probands; collectively, the cohorts span 3,429 probands, and the observed rate of de novo variation in these cohorts is significantly higher than the estimated background-mutation rate (p = 2.46 × 10-6). We also find that exome sequencing provides lower coverage and appears less sensitive to rare variation in BRSK2 than does genome sequencing; this fact most likely reduces BRSK2's visibility in many clinical and research sequencing efforts. Altogether, our results implicate damaging variation in BRSK2 as a source of neurodevelopmental disease.

Keywords: BRSK2; Mendelian disease; clinical sequencing; de novo; developmental delay; exome; genome; intellectual disability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Autistic Disorder / genetics
  • Child
  • Child Behavior Disorders / genetics
  • Child, Preschool
  • Developmental Disabilities / genetics*
  • Exome
  • Exome Sequencing
  • Female
  • Gene Deletion*
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heterozygote
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Motor Skills Disorders / genetics
  • Mutation
  • Neurodevelopmental Disorders / genetics*
  • Phenotype
  • Protein Serine-Threonine Kinases / genetics*
  • Young Adult


  • Brsk2 protein, human
  • Protein Serine-Threonine Kinases