Duplications at 19q13.33 in patients with neurodevelopmental disorders

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http://hdl.handle.net/10138/301618

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Perez-Palma , E , Saarentaus , E , Ravoet , M , De Ferrari , G V , Nuernberg , P , Isidor , B , Neubauer , B A & Lal , D 2018 , ' Duplications at 19q13.33 in patients with neurodevelopmental disorders ' , Neurology Genetics , vol. 4 , no. 1 , 210 . https://doi.org/10.1212/NXG.0000000000000210

Title: Duplications at 19q13.33 in patients with neurodevelopmental disorders
Author: Perez-Palma, Eduardo; Saarentaus, Elmo; Ravoet, Marie; De Ferrari, Giancarlo V.; Nuernberg, Peter; Isidor, Bertrand; Neubauer, Bernd A.; Lal, Dennis
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
Date: 2018-02
Language: eng
Number of pages: 7
Belongs to series: Neurology Genetics
ISSN: 2376-7839
URI: http://hdl.handle.net/10138/301618
Abstract: Objective After the recent publication of the first patients with disease-associated missense variants in the GRIN2D gene, we evaluate the effect of copy number variants (CNVs) overlapping this gene toward the presentation of neurodevelopmental disorders (NDDs). Methods We exploredClinVar (number ofCNVs = 50,794) andDECIPHER (number ofCNVs = 28,085) 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 11 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 NDDs and dysmorphic features as the most common clinical phenotype (N = 8/11), followed by seizures (N = 6/11) and intellectual disability (N = 5/11). 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 4 genes for future evaluation: CARD8, C19orf68, KDELR1, and GRIN2D, which are promising candidates for disease causality. Furthermore, investigation of the literature especially supports GRIN2D as the best candidate gene. Conclusions Our study presents dup19q13.33 as a novel duplication syndrome locus associated with NDDs. CARD8, C19orf68, KDELR1, and GRIN2D are promising candidates for functional follow-up.
Subject: EPILEPSY
MUTATIONS
VARIANTS
TRISOMY
HUMANS
3112 Neurosciences
1184 Genetics, developmental biology, physiology
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