Genomic loss of NR4A2 was first reported in relation to complex neurodevelopmental disorder in 2013 (PMID: 23554088). Affected individuals present with developmental delays, language impairment, intellectual disability, autism, epilepsy, and ataxia, with dystonia. Parkinsonism is also reported in early adulthood in some individuals (PMID: 31922365). To date, 8 unique de novo variants predicted to cause loss of function of the protein have been reported. Multiple de novo missense variants in the DNA binding domain of the protein have also been described in affected individuals in the literature (PMIDs: 30504930, 32366965). In addition to SNVs and indels, whole-gene deletions involving only NR4A2 have also been identified (PMIDs: 28544326, 29770430). This gene is intolerant to loss-of- function variants, as indicated by its pLI score of 1 in gnomAD (v2.1.1). This gene-disease relationship is supported by mouse models with conditional gene targeting showing loss of striatal dopamine neurons, neuron degeneration, and impaired motor function (PMID: 20016108). In summary, NR4A2 is definitively associated with complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel Expert Panel on 05/05/2021 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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