Monoallelic variants in IRF2BPL were first reported in patients with phenotypes including epilepsy, loss of speech and motor skills, progressive dysphagia, and motor features including dystonia and spasticity in 2018 (Marcogliese et al., PMID: 30057031). Patients may present with some or all of these features beginning at 3-4 months of age, or as late as the fifth decade of life. In the literature, assertions have been made for a relationship between IRF2BPL and at least three different autosomal dominant entities: progressive myoclonus epilepsy; developmental and epileptic encephalopathy; and neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in phenotypic variability, mode of inheritance, and variant type. Therefore, we are lumping these three entities into one, autosomal dominant neurodegenerative disease (MONDO:0005559).
Twenty-one variants (nonsense and frameshift) that have been reported in 27 probands in 11 publications are included in this curation (PMIDs: 36810721, 30057031, 31621620, 30166628, 37114479, 31583567, 37346291, 34864472, 36127562, 31432588, 32427350). Of note, the majority of reported variants have been de novo; parental testing was unavailable for the remaining individuals.
In summary, there is definitive evidence supporting the relationship between IRF2BPL and autosomal dominant neurodegenerative disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date September 5, 2023 (SOP Version 9).
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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