Abstract
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 language | English |
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Pages (from-to) | 346-356 |
Number of pages | 11 |
Journal | American Journal of Human Genetics |
Volume | 108 |
Issue number | 2 |
DOIs | |
Publication status | Published - 4 Feb 2021 |
Keywords
- MISSENSE MUTATIONS
- BINDING PROTEIN
- EXPRESSION
- INTERLEUKIN-2
- CHROMATIN
- REGION
- GENES