The GATAD2A protein is part of the NuRD complex, which is a multiprotein complex that is intrinsically involved in cellular regulation of gene expression and cellular differentiation. One basic role GATAD2A has (similar to GATAD2B) is as a bridge between the different parts of the NuRD complex. Disruption of this bridging role likely disrupts NuRD function and decreases NuRD activity.
GARND is due to this decreased NuRD activity altering gene expression and regulation during embryogenesis. As GATAD2A is likely the predominant type of GATAD2 protein in early development, this may lead to severe disruptions in embryonic development that may interfere with development of the fetus. Whether this causes embryonic demise is unclear, although the extremely rare incidence of GARND may lend credence to this concept.
GATAD2A is also present during creation of neurons and the brain and although it is not the predominant GATAD2 paralog making up NuRD complexes during those periods (compared to GATAD2B), it likely also has an effect on brain development as seen in patients with global delays and structural brain anomalies.
Some GARND children have some clinical findings that are similar to another disorder involving NuRD. Termed GAND, this disease is associated with the GATAD2Bgene, which is closely related to GATAD2A. GATAD2A and GATAD2B proteins cannot be in the same NuRD complexes, but form different NuRD subtypes (GATAD2A-NuRD and GATAD2B-NuRD, respectively).
Whether these related GATAD2 proteins have redundant and/or exclusive functions is under study, but their phenotypic similarities indicate there are likely some overlapping roles.
The GATAD2Avariants in the reported cohort were very similar to variants seen in GAND, the disorder associated with GATAD2B. It seems that GATAD2A and GATAD2B are similar, but are expressed at different time periods.
All of this information indicate that although these variants produce diverse clinical presentations, these variants are likely pathogenic and involved in GARND. Future research dissecting the regions of GATAD2Aand its clinical counterpart are ongoing.
GATAD2A