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

The DDD Study

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

23 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)346-356
Aantal pagina's11
TijdschriftAmerican Journal of Human Genetics
Volume108
Nummer van het tijdschrift2
DOI's
StatusGepubliceerd - 4 feb. 2021

Vingerafdruk

Duik in de onderzoeksthema's van 'Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction'. Samen vormen ze een unieke vingerafdruk.

Citeer dit