Submission Details

Autosomal dominant

06/12/2019

The GATAD2B gene is located on chromosome 1 at 1q21.3 and encodes the GATA zinc finger domain containing 2B protein, a transcriptional repressor. GATAD2B is a component of the methyl-CpG-binding protein-1 complex, which is involved in the deacetylation of methylated nucleosomes. GATAD2B was first reported in relation to autosomal dominant intellectual disability in 2013 (23033978: de Ligt et al. 2012). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least seven probands in five publications (23033978: de Ligt et al. 2012; 23644463: Willemsen et al. 2013; 28077840: Luo et al. 2017; 30346093: Rabin et al. 2018; 30482549: Ueda et al. 2019). All cases were heterozygous for predicted loss of function variants, and variants were confirmed or assumed de novo in all cases, although in two cases, the proband’s healthy mother was noted to be low-level mosaic for the variant. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Haploinsufficiency is implicated as the mechanism of disease. This gene-disease relationship is supported by limited animal model data. Pan-neuronal siRNA knockdown (to ~30% of wildtype) of the GATAD2 homolog in drosophila lead to a deficit in habituation, which was used as a measure of intellectual disability (23644463: Willemsen et al. 2013). Knockdown flies also showed evidence of synaptic structure abnormalities in larval neuromuscular junction, implicating a role of the protein in synaptic function. In summary, there is strong evidence to support the relationship between GATAD2B and autosomal dominant intellectual disability. Although the association has been repeated demonstrated in the clinical diagnostic setting, additional experimental evidence is needed to reach a definitive classification.

30346093 23033978 23644463 28077840 30482549