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.

Original languageEnglish
Pages (from-to)346-356
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number2
Early online date28 Jan 2021
Publication statusPublished - 4 Feb 2021


  • HPO-based analysis
  • SATB1
  • cell-based functional assays
  • de novo variants
  • intellectual disability
  • neurodevelopmental disorders
  • seizures
  • teeth abnormalities


Dive into the research topics of 'Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction'. Together they form a unique fingerprint.

Cite this