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De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy.

Genet Med. 2020 May 5. doi: 10.1038/s41436-020-0815-4. [Epub ahead of print]

Authors/Editors: Singh S, Gupta A, Zech M, Sigafoos AN, Clark KJ, Dincer Y, Wagner M, Humberson JB, Green S, van Gassen K, Brandt T, Schnur RE, Millan F, Si Y, Mall V, Winkelmann J, Gavrilova RH, Klee EW, Engleman K, Safina NP, Slaugh R, Bryant EM, Tan WH, Granadillo J, Misra SN, Schaefer GB, Towner S, Brilstra EH, Koeleman BPC.
Publication Date: 2020



Purpose This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene.

Methods Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher.

Results Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay.

Conclusion Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients.

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