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

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. Contrastingly, 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 and encode truncated proteins, 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. 3. CC-BY 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in

Heterogeneity in Fragile X Syndrome Highlights the Need for Precision Medicine-Based Treatments

“…Further complexifying matters: well-defined clinical entities can be caused by mutations in several genes (as it is the case for Noonan syndrome, linked to mutations in 14 different genes) ( 12 ), while mutations occurring in a same gene can result into a wide spectrum of symptoms, as exemplified by MECP2 mutations in Rett syndrome ( 13 ). Adjunctly, different kinds of mutations can result in different pathophysiological mechanisms, as recently exemplified by mutations in SATB1 , in which three different kinds of variants were associated to distinct pathological consequences ( 14 ).…”

Genotype–Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results

“…In addition, other severe clinical features as spasticity, hypotonia, and epilepsy were significantly more common in patients with missense variants than in patients with PTVs. These observations were confirmed by the authors using a partitioning around medoids clustering algorithm [ 21 ] based on 100 features derived from standardized clinical data: the individuals were clustered into two separate clinical groups, one with PTVs and the other with missense variants [ 7 ]. Computational analysis of facial features also supported the existence of two separate clinical groups: patients with missense variants had a different facial gestalt from individuals carrying PTVs.…”

“…As expected, SATB1 and SATB2 patients display very strong overlapping phenotypes. However, subtle differences in the neurological phenotype have been reported: absence of speech and drooling seem to be more common in patients with SATB2 variants, whereas epilepsy seems to be more common in patients with SATB1 variants, especially in patients with missense variants, as previously discussed [ 7 ].…”

“…Recently SATB1 disrupting de novo pathogenetic variants has been identified in patients affected by NDD, suggesting a role for this gene also in neurodevelopment [ 1 , 20 ]. Den Hoed and colleagues [ 7 ] have just published a case series of 42 individuals with pathogenetic or likely pathogenetic SATB1 variants. Of these variants, twenty-eight were de novo, three were inherited from an affected parent, two were inherited from unaffected parent (reduced penetrance), five were probably due to parental mosaicism, and for the last four, inheritance could not be established.…”

Molecular networks of the FOXP2 transcription factor in the brain

“…Repression of BCL11B in SATB2‐positive neurons is an essential mechanism in cortical lamination, resulting in upper‐layer neuron specification (Britanova et al , 2008 ). In humans, YY1 (MIM #617557), SATB1 (MIM # 619228 and #619229), and SATB2 (MIM #612313) are all implicated in neurodevelopmental disorders (Bengani et al , 2017 ; den Hoed et al , 2021 ; Gabriele et al , 2017 ). Notably, SATB2 mutations cause severe language impairments (Zarate & Fish, 2017 ).…”