The original study indicated that mutations can lead to diverse effects on protein function. Evaluation of nonsynonymous changes in zebrafish pointed to a dominant toxic effect for some variants and a haploinsufficiency mechanism for the others. These observations, combined with the observed genetic heterogeneity (missense or truncating mutations, copy number variant (CNV) deletions or duplication), suggests a complex molecular basis of pathology, which is not yet fully understood. Additionally, the relatively small number of affected individuals identified so far precludes accurate determination of the genotype-phenotype correlation inferred from the preliminary data.
Notably, a subset of individuals from the original RORA report display epilepsy. This clinical feature was not investigated thoroughly in the preliminary study, whereas mutations of the paralog, RORB, were shown previously to cause behavioral and cognitive impairment as well as epilepsy (Rudolf et al. 2016).
To investigate epilepsy further in individuals with RORA or RORB, we designed a follow-up study aiming to:
- Identify additional affected patients with mutations in RORA.
- Refine and/or expand the clinical spectrum associated with RORA mutations.
- Compare the phenotype in epileptic patients having a mutation or a CNV deletion of RORA or RORB.
To participate in the study we require:
- Genetic and clinical information, including clinical brain imaging data and EEGs (mandatory).
- Patient-derived primary skin fibroblasts, skin biopsy or blood (optional).
Clinicians can submit clinical data directly into the database.
Instructions for the clinician who will be involved:
- Please request written consent for the use and storage of medical information with or without photographs.