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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 publication

DOI

10.1016/j.ajhg.2021.01.007

Type

Journal article

Journal

Am J Hum Genet

Publication Date

04/02/2021

Volume

108

Pages

346 - 356

Keywords

HPO-based analysis, SATB1, cell-based functional assays, de novo variants, intellectual disability, neurodevelopmental disorders, seizures, teeth abnormalities, Chromatin, Female, Genetic Association Studies, Haploinsufficiency, Humans, Male, Matrix Attachment Region Binding Proteins, Models, Molecular, Mutation, Mutation, Missense, Neurodevelopmental Disorders, Protein Binding, Protein Domains, Transcription, Genetic