Search

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.

The Jumonji domain containing 1C (JMJD1C) gene encodes the Jumonji domain-containing protein 1C (JMJD1C) and is a member of the jmJC domain-containing protein family involved in histone demethylation that is expressed in the brain. We report seven, unrelated patients with developmental delays or intellectual disability and heterozygous, de novo sequence variants in JMJD1C. All patients had developmental delays, but there were no consistent additional findings. Two patients were reported to have seizures for which there was no other identified cause. De novo, deleterious sequence variants in JMJD1C have previously been reported in patients with autism spectrum disorder and a phenotype resembling classical Rett syndrome, but only one JMJD1C variant has undergone functional evaluation. In all of the seven patients in this report, there was a plausible, alternative explanation for the neurocognitive phenotype or a modifying factor, such as an additional potentially pathogenic variant, presence of the variant in a population database, heteroplasmy for a mitochondrial variant or mosaicism for the JMJD1C variant. Although the de novo variants in JMJD1C are likely to be relevant to the developmental phenotypes observed in these patients, we conclude that further data supporting the association of JMJD1C variants with intellectual disability is still needed., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)