Perez-Palma, Eduardo ORCID: 0000-0003-0546-5141, Saarentaus, Elmo ORCID: 0000-0002-8475-7187, Ravoet, Marie, De Ferrari, Giancarlo V., Nuernberg, Peter, Isidor, Bertrand, Neubauer, Bernd A. and Lal, Dennis (2018). Duplications at 19q13.33 in patients with neurodevelopmental disorders. Neurol.-Genet., 4 (1). PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 2376-7839

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Perez-Palma, EduardoUNSPECIFIEDorcid.org/0000-0003-0546-5141UNSPECIFIED
Saarentaus, ElmoUNSPECIFIEDorcid.org/0000-0002-8475-7187UNSPECIFIED
Ravoet, MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Ferrari, Giancarlo V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isidor, BertrandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neubauer, Bernd A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-196898
DOI: 10.1212/NXG.0000000000000210
Journal or Publication Title: Neurol.-Genet.
Volume: 4
Number: 1
Date: 2018
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 2376-7839
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EPILEPSY; MUTATIONS; VARIANTS; TRISOMY; HUMANSMultiple languages
Genetics & Heredity; Clinical NeurologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19689

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