RT Journal Article
SR Electronic
T1 Duplications at 19q13.33 in patients with neurodevelopmental disorders
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e210
DO 10.1212/NXG.0000000000000210
VO 4
IS 1
A1 Pérez-Palma, Eduardo
A1 Saarentaus, Elmo
A1 Ravoet, Marie
A1 De Ferrari, Giancarlo V.
A1 Nürnberg, Peter
A1 Isidor, Bertrand
A1 Neubauer, Bernd A.
A1 Lal, Dennis
YR 2018
UL http://ng.neurology.org/content/4/1/e210.abstract
AB 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 explored ClinVar (number of CNVs = 50,794) and DECIPHER (number of CNVs = 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.DD=developmental delay; ID=intellectual disability; LoF=loss of function; NDD=neurodevelopmental disorder