RORB was first reported in individuals with autosomal dominant epilepsy in 2016 (Rudolf et al., PMID: 27352968). One international collaboration reported a large cohort of 35 individuals with RORB variants; these individuals were reported to primarily have absence and generalized epilepsy onset in the first decade of life, with mild-to-moderate intellectual disability (PMID:38165337). Approximately 85% of patients have intellectual disability, 25% have autism spectrum disorder, and 25% have attention deficit/hyperactivity disorder (PMID:38165337). Evidence supporting this gene-disease relationship includes case-level data. At least 35 variants (e.g. missense, nonsense, frameshift, large deletion, etc) have been reported in probands in 3 publications (PMIDs: 27352968, 32162308, 38165337). Variants in this gene segregated with disease in 11 additional family members. The mechanism for disease is likely haploinsufficiency (PMIDS: 27352968, 38165337). In summary, there is definitive evidence to support the relationship between RORB and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This gene-disease relationship was originally evaluated by the Epilepsy GCEP on September 20, 2022. It was re-evaluated May 21, 2024. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of new case-level data (PMID: 38165337). Additionally, the disease term for this curation was updated from epilepsy (MONDO:000502) to complex neurodevelopmental disorder (MONDO:0100038) to better capture the neurodevelopmental phenotypes reported in patients, such as intellectual disability, autism, ADHD, and developmental delays.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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