Submission Details

The SATB2 (Special AT-rich sequence-Binding protein 2) gene encodes a DNA-binding protein that specifically binds to genomic nuclear matrix attachment regions and participates in transcriptional regulation and chromatin remodeling. This highly conserved gene encodes a protein with a N-terminal ubiquitin-like oligomerization domain, two CUT DNA binding motifs and a C-terminal homeodomain. This gene curation is for autosomal dominant SATB2-associated disorder (MONDO:0100147). Heterozygous pathogenic variants in SATB2 have been observed in individuals with intellectual disability, global developmental delay, speech delay, craniofacial dysmorphology, cleft palate, drooling, hypotonia, skeletal and dental anomalies [PMID: 31021519]. Evidence supporting this gene-disease relationship includes case-level data and experimental data. There are more than 150 affected individuals reported in the literature to date [PMID: 31021519]. Nearly all cases are de novo; however, there are at least 3 reports of sibling recurrence of this disorder, indicating gonadal mosaicism in one of the parents [PMID: 28151491, 31333717, 31425298]. A spectrum of SATB2 variants including frameshift, nonsense, splice, missense, in-frame insertions, and intragenic deletions have been reported [PMIDs: 28151491, 29436146, 31021519]. The postulated disease mechanism is loss of function, though there has been a report of a nonsense variant (exon 8 of 12) shown to escape nonsense-mediated decay, and thought to cause disease as the result of a dominant negative effect [PMID: 17377962, 23925499]. Currently, only a few SATB2 missense variants have been assessed by studies for aberrant function [PMID: 31021519]. In experimental evidence, molecular function and animal models support this gene-disease association. In human K562 erythroid cells, chromatin immunoprecipitation experiments using anti-Satb2 antibody confirmed direct Satb2 DNA binding on a matrix attachment region, in the globin locus, [PMID: 22825848]. Multiple mouse models including Satb2+/- & Satb2-/- whole body knockouts and conditional knockouts (brain) have been published [PMIDs: 16751105, 16960803, 18255030, 18255031, 27478017, 27897969, 30809123]. These models recapitulated the neurological, craniofacial, dental and bone anomalies seen in SATB2 associated disorder. Notably, whole body Satb2-/- knockout results in perinatal lethality [PMIDs: 16751105, 16960803]. Conditional knockout of Satb2 in cortex and hippocampus resulted in adult mice which showed hyperactivity, increased impulsivity, altered social interaction behaviors, abnormal social novelty, impaired spatial learning and memory [PMID: 30809123]. In summary, SATB2 is definitively associated with autosomal dominant SATB2-associated disorders. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The ClinGen Intellectual Disability and Autism Gene Curation Expert Panel approved this classification on 9/15/2020 (SOP Version 7).