Purpose: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND).
Methods: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex.
Results: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners.
Conclusions: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.
Keywords: GATAD2B; NuRD complex; apraxia of speech; chromatin remodeling; macrocephaly.
The NuRD Complex and Macrocephaly Associated Neurodevelopmental DisordersTM Pierson et al. Am J Med Genet C Semin Med Genet 181 (4), 548-556. PMID 31737996.The nucleosome remodeling and deacetylase (NuRD) complex is a major regulator of gene expression involved in pluripotency, lineage commitment, and corticogenesis. This im …
Intellectual Disability Due to Monoallelic Variant in GATAD2B and Mosaicism in Unaffected ParentR Rabin et al. Am J Med Genet A 176 (12), 2907-2910. PMID 30346093. - Case ReportsThe GATA zing finger domain-containing protein 2B (GATAD2B) gene encodes the p66beta protein, a subunit of the MeCP1-Mi2/ nucleosome remodeling and deacetylase complex, w …
GATAD2B-related Intellectual Disability Due to Parental Mosaicism and Review of LiteratureP Kaur et al. Clin Dysmorphol 28 (4), 190-194. PMID 31205050. - ReviewGATA zinc finger domain-containing 2B (GATAD2B) encodes p66beta, a subunit of transcription repressor complex methyl-CpG-binding protein-1 histone deacetylase complex/nuc …
Correction: GATAD2B-associated Neurodevelopmental Disorder (GAND): Clinical and Molecular Insights Into a NuRD-related DisorderC Shieh et al. Genet Med. PMID 32047287.An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Towards Elucidating the Stability, Dynamics and Architecture of the Nucleosome Remodeling and Deacetylase Complex by Using Quantitative Interaction ProteomicsSL Kloet et al. FEBS J 282 (9), 1774-85. PMID 25123934. - ReviewMBD3 physically interacts with ZNF512B, HDAC1, ZMYND8, GATAD2B, SALL4, GATAD2A, ZNF592, MTA3, ZNF687, CDK2AP1, CHD3, ZNF532, HDAC2, MTA2, CHD4, MTA1, KPNA2, CHD5, RBBP4 a …