ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
28544326 Reuter et al 2017 described a female with mild intellectual disability and speech and language impairment. CMA testing detected a 89 kb de novo deletion of 2q24.1 with included only the gene NR4A2. A second small deletion at 1p36.33 was also detected but was inherited from the healthy mother.
29770430 Levy et al 2018 reported two patients with focal deletions of NR4A2. The first patient had mild to moderate intellectual disability and autism spectrum disorder. Patient 2 had global developmental delay and language deficits. Both patients were found to have de novo deletions of NR4A2 by CMA.
31428396 Ramos et al 2019 reported a de novo frameshift variant in NR4A2 (p.Ser110Valfs*2) in a patient with epilepsy, language impairment and intellectual disability.
32366965 Singh et al 2020 reported three patients with likely loss-of-functions variants in NR4A2. All three patients had global developmental delay, speech and language impairment, and hypotonia. Two patients also had seizures. Two variants (c.865-1_865delGCinsAAAAAGGAGT and p.Q109Pfs*3) were confirmed de novo. A nonsense variant (p.E526*) was not detected in the mother but the father was unavailable for testing.
31922365 Wirth et al 2020 reported loss of function variants in two patients with mild intellectual disability who developed dystonia parkinsonism in early adulthood. Patient one had a history of mild intellectual disability with prominent language impairment in childhood. He developed seizures and paroxysmal episodes of generalized dystonia in early adulthood. This patient carried the same NR4A2 p.Ser110Valfs*2 variant reported in Ramos et al 2019. The variant was not present in the asymptomatic parents, brother, and sister. Patient 2 had a history of mild intellectual disability. At age 30 she developed tremors and progressed to an early-onset dystonia parkinsonism syndrome. A frameshift variant in NR4A2 (p.Asn294fs) was identified, however, inheritance could not be assessed. The authors suggest dystonia may be a later onset symptom in patients with NR4A2 pathogenic variants.

Haploinsufficiency phenotype comments:

Deletion or loss of function variants in NR4A2 have been reported in multiple individuals with mild to moderate intellectual disability and language impairment. Other phenotypes may include seizures and early adult onset dystonia. Even though numerous cases have been reported, some of the probands had limited additional testing to rule out other possible causes of neurodevelopmental disorders. Additionally, parental relationships were not reported to be confirmed for several of the de novo cases. Additional case examples are needed to clarify the relationship between haploinsufficiency and disease.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity