NR4A2 – Neurodevelopmental Disorder

The association between NR4A2 and neurodevelopmental disorder is supported by multiple unrelated patients harboring de novo variants. A cohort study described nine unrelated probands (PMID:32366965) presenting with global developmental delay, hypotonia, and epilepsy. De novo status was confirmed in eight patients (PMID:32366965), and one larger deletion encompassed adjacent genes. Phenotypes were consistent across patients, with six exhibiting hypotonia (PMID:32366965) and six experiencing seizures (PMID:32366965). Targeted RNA sequencing in one case demonstrated aberrant splicing leading to likely nonsense-mediated decay, underscoring loss-of-function as a mechanism.

Inheritance is autosomal dominant with de novo occurrence of pathogenic NR4A2 alleles. Across the nine probands, four distinct variants were identified: three missense and one frameshift, consistent with haploinsufficiency. The variant spectrum includes c.968G>T (p.Cys323Phe) among others, and no recurrent or founder alleles have yet been described. Segregation beyond the de novo events was not observed.

Functional data corroborate the genetic findings. The splicing variant confirmed by RNA analysis resulted in abnormal transcripts predicted to undergo degradation. Nurr1 null mice lack midbrain dopaminergic neurons and exhibit perinatal lethality, phenocopying aspects of the human neurodevelopmental phenotype. NR4A2 encodes a transcription factor essential for neuronal differentiation, and loss of one allele aligns with the dominant-negative or haploinsufficient model observed in patients.

No published reports have refuted the NR4A2–neurodevelopmental disorder connection. Studies in psychiatric and movement disorders have identified polymorphisms and rare variants without clear segregation or functional validation, but these do not contradict the de novo findings in pediatric cases.

Integration of genetic and functional evidence establishes a strong causal relationship. De novo protein-altering NR4A2 variants consistently yield neurodevelopmental impairment, with RNA studies confirming transcript instability. The animal model phenotypes and molecular data align with human clinical features, indicating a loss-of-function mechanism.

Key take-home: De novo heterozygous NR4A2 variants cause a recognizable autosomal dominant neurodevelopmental disorder, supporting diagnostic testing and informing future therapeutic development.

References

• Genetics in Medicine • 2020 • De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy. PMID:32366965

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