Intellectual Developmental Disorder With Or Without Epilepsy Or Cerebellar Ataxia

A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with or without epilepsy or cerebellar ataxia (IDDECA) is caused by heterozygous mutation in the RORA gene (600825) on chromosome 15q22.

Clinical Features

Guissart et al. (2018) reported 11 unrelated patients with syndromic intellectual disability. The severity was variable. Some patients had mild borderline intellectual disability with mild speech delay or normal speech, whereas others had severe cognitive impairment with poor or absent speech. Most had delayed motor development and delayed walking. Most had ataxia, hypotonia, poor coordination, and/or mild tremor, suggesting cerebellar dysfunction. Three patients had documented cerebellar hypoplasia or pontocerebellar atrophy on brain imaging. Seven patients had seizures of variable types, including neonatal myoclonic, tonic-clonic, multifocal, generalized, and absence. Five patients were diagnosed with autism spectrum disorder. More variable features included strabismus, esotropia, nystagmus, and oculomotor apraxia.

Molecular Genetics

In 11 unrelated patients with IDDECA, Guissart et al. (2018) identified heterozygous mutations in the RORA gene (see, e.g., 600825.0001-600825.0005). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing when possible. All mutations were confirmed to occur de novo, except in 1 adopted patient. The patients were ascertained through collaboration between several research centers. There were 5 missense mutations, 4 frameshift mutations, a splice site mutation, and a nonsense mutation. Two of the missense variants (S409R and R462Q) mapped to the ligand-binding domain, and 3 (G92A, K94R, and C90S) mapped to the DNA-binding domain. Knockdown of the zebrafish ortholog of the rora gene (roraa) resulted in decreased cerebellar volume with a decreased size of Purkinje and granule cell layers compared to wildtype. In vivo complementation studies in roraa-null zebrafish showed that wildtype human RORA could rescue the cerebellar phenotype. Expression of 2 of the human missense mutations in the DNA-binding domain (G92A and K94R) resulted in early developmental defects, including increased mortality, reduction in the size of anterior structures, and tail extension failure. The phenotype was more severe than the morphant phenotype, suggesting a dominant toxic effect. In contrast, expression of the R462Q missense variant in the ligand-binding domain did not cause morphologic defects and did not rescue the cerebellar defect, suggesting that this mutation resulted in a loss of function. Guissart et al. (2018) suggested that the mutations have different pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect depending on their localization in the ligand-binding domain or the DNA-binding domain, respectively.

Genotype/Phenotype Correlations

Guissart et al. (2018) observed that patients with loss-of-function RORA mutations tended to have mild intellectual disability with autistic features, whereas 3 individuals with potentially dominant toxic variants had more severe intellectual disability and motor abnormalities, including cerebellar ataxia. However, there was significant phenotypic overlap among the patients.