Table 1.
Clinical phenotypes of patients with heterozygous de novo and putative de novo NR4A2 variants.
| Patient | Variant (NM_006186.3) | Inheritance | Protein domain/region | Seizures | Age, years/sex/age at seizure onset | Developmental delay | Speech and language impairment | Motor delay | Intellectual disability | Behavioral problems | MRI findings | Neurologic examination findings | Other |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | c.839G>A, p.C280Y | De novo | ZnF_C4 domain, DNA binding domain | Yes | 15/F/6.5 years | Global | NA | NA | Severe | Autism | Normal | Normal | Sleeping difficulties |
| 2 | c.865-1_865delGCinsAAAAAGGAGT, p.? | De novo | ZnF_C4 domain, DNA binding domain | Yes | 12/M/10 years | Global | Yes | Yes | Mild | Hyperactivity, anxiety | Normal | Mild hypotonia | EDS hypermobility |
| 3 | c.914G>A, p.C305Y | De novo | ZnF_C4 domain, DNA binding domain | Yes | 9/F/NA | Moderate | NA | NA | Mild to moderate | NA | Gliosis | Choreoathetoid movements, dystonia, ataxic gait | NA |
| 4 | c.1175A>G, p.D392G | De novo | Hinge region | Yes | 3/F/5 months | Global | NA | NA | Severe | No | Moderate cerebellar atrophy | Severe hypotonia, feeding difficulties, dystonia | None |
| 5 | c.1576G>T, p.E526* | NA | HOLI, ligand binding domain | No | 5/M/Never | Global | Yes | Yes | Mild | Attachment disorder, hyposensitivity | NA | Mild hypotonia, no movement disorder | No |
| 6 | c.325dupC, p.Q109Pfs*3 | De novo | N-terminal regulatory domain | Yes | 2/M/6 months | Global | Yes | Yes | NA | Sensory sensitivity | Pontine hypoplasia, ventriculomegaly | Severe hypotonia, feeding difficulties | Facial dysmorphism, sleep disordered breathing |
| 7 | c.857T>C, p.F286S | De novo | ZnF_C4 domain, DNA binding domain | No | 4/F/Never | Global | Yes | Yes | Moderate | No | Normal | Hypotonia | Mild joint hypermobility, shagreen spot and hypopigmented spot |
| 8 | c.968G>T, p.C323F | De novo | ZnF_C4 domain, DNA binding domain | No | 19/F/Never | Global | Yes | Yes | Moderate to severe | No | Normal | Mild generalized hypotonia | Facial dysmorphism, joint hypermobility |
| 9 | arr[GRCh37]2q23.3q24.1(154790212_158488241)x1 | De novo | NA | yes | 43/M/13 years | Moderate | NA | NA | Moderate to severe | Hyperactivity, aggression | Enlarged cerebrospinal fluid spaces | Progressive ataxia in adulthood | No |
AED antiepileptic drug, EDS Ehlers–Danlos syndrome, EEG electroencephalogram, F female, M male, MRI magnetic resonance image, NA not assessed.