Novel Intragenic Duplication of GATAD2B in a Patient With GAND

The nucleosome remodeling and deacetylation (NuRD) complex is a major chromatin regulator and plays a critical role in regulating gene transcription, genome integrity, and cell cycle progression. Heterozygous variants in GATAD2B, a core NuRD component, have been reported to cause GATAD2B-Associated Neurodevelopmental Disorder (GAND), an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, developmental delay, hypotonia, and distinctive craniofacial features. The vast majority of disease-causing variants in GATAD2B reported to date are loss-of-function (nonsense, frameshift, or splice site) variants. Here, we report a 6-year-old male patient with profound global developmental delay and dysmorphic features, who was found to have a de novo ~97 kbp partial duplication of the GATAD2B gene. Using long-read transcriptome and genome sequencing on the Pacific BioSciences (PacBio) platform, we show that the duplication is a tandem event whose breakpoint in the 3' UTR of the gene causes skipping of the last exon and transcriptional read-through. The resulting transcript contains two incomplete copies of GATAD2B, one with exons 1-10 and the other with exons 2-7, likely representing a loss-of-function allele. Follow-up clinical evaluations confirmed the patient's diagnosis of GAND, ending a years-long diagnostic odyssey for the family and highlighting an unusual mechanism of gene disruption in GATAD2B.