Submission Details

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 NuRD complex, which is involved in the deacetylation of methylated nucleosomes. GATAD2B was first reported in relation to a recognizable autosomal dominant severe intellectual disability, poor language, strabismus, grimacing face, long fingers syndrome in 2013 (Willemsen et al., 2013, PMID: 23644463), although variants in individuals with intellectual disability were reported earlier (de Ligt et al., 2012, PMID: 23033978). This disorder, which is also referred to as GAND, or GATAD2B-associated neurodevelopmental syndrome, is characterized by infantile hypotonia, feeding issues, developmental delay, severe ID, impaired speech, macrocephaly, gait abnormalities, abnormal brain MRI, delayed toilet training, strabismus, and dysmorphic facial features that include prominent forehead, hypertelorism, prominent/bulbous nasal tip, pointed chin. More than 50 cases have been described (PMIDs: 23644463, 23033978, 28077840, 30346093, 30482549, 32688057, 31949314, 25356899, 27159321, 31205050). Nonsense, frameshift, splice, intragenic deletions, and a small number of missense variants clustered in conserved region domains have been reported. Variants occurred de novo in the majority of cases, with a handful of reports of parental mosaicism. Seven variants that were reported in seven probands from five publications are included in this curation (PMIDs: 32688057, 30482549, 30346093, 28077840, 23644463). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is known to be haploinsufficiency/loss of function. This gene-disease relationship is also supported by a biochemical function in the NuRD complex shared with two other genes, CHD3 and CHD4, that are associated with neurodevelopmental syndromes with overlapping features, impaired habituation, and altered synapse structure in a pan-neuronal knockdown Drosophila model, and evidence of disrupted NuRD protein-protein interactions for reported missense variants (PMIDs: 31949314, 23644463). In summary, GATAD2B is definitively associated with autosomal dominant severe intellectual disability, poor language, strabismus, grimacing face, long fingers syndrome. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 2/1/2022 (SOP Version 8).