Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Am J Hum Genet. 2021 Feb 4;108(2):346-356. doi: 10.1016/j.ajhg.2021.01.007. Epub 2021 Jan 28.


Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Keywords: HPO-based analysis; SATB1; cell-based functional assays; de novo variants; intellectual disability; neurodevelopmental disorders; seizures; teeth abnormalities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin / metabolism
  • Female
  • Genetic Association Studies
  • Haploinsufficiency
  • Humans
  • Male
  • Matrix Attachment Region Binding Proteins / chemistry
  • Matrix Attachment Region Binding Proteins / genetics*
  • Matrix Attachment Region Binding Proteins / metabolism
  • Models, Molecular
  • Mutation*
  • Mutation, Missense
  • Neurodevelopmental Disorders / genetics*
  • Protein Binding
  • Protein Domains
  • Transcription, Genetic


  • Chromatin
  • Matrix Attachment Region Binding Proteins
  • SATB1 protein, human