SATB2

Inheritance Pattern: AD

Disease ID:MONDO:0012864

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012864

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0100147

Submitter: Illumina

The SATB2 gene is located on chromosome 2 at 2q33.1 and encodes the SATB homeobox 2 protein, a nuclear matrix DNA-binding protein that regulates nuclear gene expression through chromatin remodelling. SAT2B was first reported in relation to autosomal dominant SATB2 associated disorder in 2007 (17377962: Leoyklang et al. 2007). Evidence supporting this gene -disease relationship include case level data and experimental data. Variants in this gene have been reported in at least five probands in three publications (17377962: Leoyklang et al. 2007; 24301056: Docker et al. 2014; 28151491: Bengani et al. 2017). Variants occurred de novo and included three nonsense variants and a frameshift variant. Missense variants have also been associated with the disorder (28151491: Bengani et al. 2017) and more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is considered to be haploinsufficiency, although one variant has been shown to have a dominant negative effect in vitro (23925499: Leoyklang et al. 2013; 28151491: Bengani et al. 2017). The spatial and temporal expression pattern of Satb2 in the embryonic mouse and chick broadly correlates with those structures affected in cases with SATB2 associated disorder. Satb2 knockout mice recapitulate key features of the clinical disease: heterozygous Satb2 knockout mice demonstrate the early onset of craniofacial dysmorphologies such as cleft palate and incisor hypodontia and/or adontia, while homozygous mice show an exacerbated phenotype that includes skeletal malformations (16960803: Britanova et al. 2006), indicating the phenotype is dose dependent. A conditional knockout mouse model lacking expression of Satb2 in the cortex and hippocampus also recapitulated behaviour abnormalities associated with the disease (30809123: Zhang et al. 2019). In summary, SATB2 is definitively associated with autosomal dominant SATB2 associated disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic setting and has been upheld over time. Notably, 2q32-q33 deletion syndrome is associated with a similar phenotype and a multigene deletion including SATB2.

Inheritance Pattern: AD

Disease ID:MONDO:0100147

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0100147

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0012864

Submitter: G2P