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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

American journal of human genetics

Publication Date

02/2021

Volume

108

Pages

346 - 356

Addresses

Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6500 AH Nijmegen, the Netherlands; International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, 6500 AH Nijmegen, the Netherlands.

Keywords

DDD Study, Chromatin, Humans, Matrix Attachment Region Binding Proteins, Transcription, Genetic, Protein Binding, Mutation, Mutation, Missense, Models, Molecular, Female, Male, Genetic Association Studies, Haploinsufficiency, Neurodevelopmental Disorders, Protein Domains