Abstracts

Rationale: While single nucleotide and Copy Number Variants (CNV) in the NMDA receptor subunits GRIN1, GRIN2A and GRIN2B have been associated with a range of neurodevelopmental disorders (NDDs) including epillepsy, little is known about the association of GRIN2D variants and  NDDs. After recent publication of the first patients with disease associated missense variants in GRIN2D, we evaluate the effect of copy number variation (CNV) overlapping this gene towards the presentation of neurodevelopmental disorders.  Methods: We explored ClinVar (N°CNV = 41,398) and DECIPHER (N°CNV = 30,222) clinical databases of genomic variations for patients with copy number changes overlapping the GRIN2D gene at the 19q13.33 locus and evaluated their respective phenotype alongside their frequency, gene content and expression with publicly available reference databases.  Results: We identified 13 patients with microduplications at the 19q13.33 locus. The majority of CNVs arose de novo and comparable CNVs are not present in control databases. All patients were reported to have neurodevelopmental disorders and dysmorphic features as the most common clinical phenotype (N= 10/13), followed by seizures (N= 6/13) and intellectual disability (N= 5/13). All duplications shared a consensus region of 405 kb overlapping 13 genes. After screening for duplication tolerance in control populations, positive gene brain expression and gene dosage sensitivity analysis, we highlight four genes for future evaluation: CARD8, C19orf68, KDELR1 and GRIN2D, which are promising candidates for disease causality. Further, investigation of the literature especially supports GRIN2D as the best candidate gene Conclusions: Our study presents dup19q13.33 as novel duplication syndrome locus associated with neurodevelopmental disorders. CARD8, C19orf68, KDELR1 and GRIN2D are promising candidates for functional follow up Funding: Eduardo Pérez.Palma was supported by the Chilean Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) regular grant number 1140353 to Giancarlo V. De Ferrari. Dennis Lal received funds from the German Academic Exchange Service (DAAD), grant number 57073880. Bernd A. Neubauer received funding by the Deutsche Forschungsgemeinschaft (Ne 416/5-1).