GATAD2B

Inheritance Pattern: AD

Disease ID:MONDO:0014034

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014034

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014034

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014034

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014034

Submitter: Illumina

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.

Inheritance Pattern: AD

Disease ID:MONDO:0014034

Submitter: ClinGen

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., 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 syndrome, or GATAD2B-associated neurodevelopmental syndrome, is characterized by infantile hypotonia, feeding issues, developmental delay, severe intellectual disability, 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, and pointed chin. More than 50 cases have been described (PMIDs: 23033978, 23644463, 25356899, 27159321, 28077840, 30346093, 30482549, 31205050, 31949314, 32688057). 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: 23644463, 28077840, 30346093, 30482549, 32688057). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) 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: 23644463, 31949314). 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 February 1, 2022 and secondarily approved by the Syndromic Disorders Gene Curation Expert Panel on March 18, 2022 (SOP Version 8).