Early onset or syndromic epilepsy

Gene: RORA

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD Intellectual dev disorder with or without epilepsy or cerebellar ataxia. Guissart et al 2018 - 11 unrelated patients with syndromic intellectual disability - 7 had seizures of variable types - het mutations in RORA gene - functional work undertaken.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, 618060

Publications

• 29656859

Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in unrelated cases.

Created: 26 Sep 2018, 9:49 a.m.

Green List (high evidence)

Multiple affected individuals from unrelated families reported with variants in this gene and neurodevelopmental phenotypes, seizures are part of the phenotype.

Created: 20 Aug 2018, 10:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 29656859

I don't know

PMID 29656859 describes a cohort of 16 individuals from 13 families with different heterozygous RORA variants, including : 2 de novo intergenic microdeletions, 1 intragenic microdeletion, 1 de novo disrupting microduplication and nine de novo point mutations (3 truncating, 1 splice-site, 5 missense SNVs). Intellectual disability (ID) was an almost universal feature with the exception of 1 individual who however had a diagnosis of ASD. Seizures were reported in 11 (of 16 individuals). Despite the small size of their cohort, the authors propose 2 subgroups of patients, the first due to haploinsufficiency presenting with ID and autistic features and the other due to a presumed dominant toxic effect, characterized by ID, gait ataxia and cerebellar atrophy. The phenotype of ID segregated with the deletion (as well as with an intragenic DISC1 deletion) in the family reported. Mutant mice (homozygous for a Rora deletion) display gait ataxia and degeneration of cerebellar Purkinje cells. Zebrafish functional studies, support an effect in the developing cerebellum, similar to what is observed in humans. This is the first report of the RORA-related phenotypes. As a result this gene could be considered for inclusion in the panel as amber or green.

Created: 18 Aug 2018, 10:46 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, 618060

Publications

• 29656859