The GATAD2B protein is part of the NuRD complex and one basic role it has, is to be a bridge between NuRD’s CHD paralogs (where chromatin remodeling activity resides) and the Histone Deacetylase Core (via NuRD’s MBD paralogs). Disruption of this bridging role likely disrupts NuRD function and and decreases NuRD activity activity. Decreased NuRD activity is likely the main cause of GAND. Because of this tethering role and GATAD2B being the prominent GATAD2 paralog during neurodevelopment, the GAND neurologic phenotype possesses many of the features of the other NuRD-related disorders combined (CHD3-, CHD4-, and CHD5-related disorders). Therefore, GAND can be thought of as a “pan-NuRDopathy” with regards to neurodevelopment (this is likely not the case with cardiac or other organ system development).
Almost all GAND variants have been de novo, although several families have been reported in the literature and our personal experience with parental mosaicism. Frequency of parental mosaicism is currently under investigation, we have been in contact with at least >10 families identified with parental mosaicism.
GATAD2B variants are of a diverse range in variant types, which in our initial publication had 2/3 of variant being nonsense and truncating frameshift variants. Other variant types were present as well with splice-site variants (16%), intragenic deletions (6%) and missense variants (12%).
Initially, all of the missense variants were located within the two conserved region domains (CR1 and CR2), of the GATAD2B protein.
GAND seems to be the result of haploinsufficiency of the GATAD2B protein (also known as p66-beta) as seen in the GAND mouse and in unpublished data using patient-derived IPS cells with loss-of-function variants.
Previously reported missense variants in CR1 and CR2 interrupt NuRD interactions between the GATAD2B protein and the CHD paralogs (CR2) and the MBD paralogs (CR1).
The neurologic phenotypes of GAND seem to involve the disorganization of the laminar cortex as a result of decreased NuRD activity. NuRD and SATB2 have previously been shown to interact to repress CTIP2 expression.
Diagnostic testing when there is a suspicion of GAND can include intellectual disability gene panels, exome sequencing, and whole genome sequencing. There is a polygenic deletion syndrome involving chromosome 1q21.3 that causes a GAND+ phenotype that can be identified through chromosomal microarray analysis.
GATAD2B