Submission Details

Autosomal dominant

08/14/2019

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.

17377962 24301056 28151491 21089028 30809123 16960803