EML1 was first reported in relation to autosomal recessive EML1-related ribbon-like subcortical heterotopia in 2014 (Kielar et al., PMID: 24859200). EML1-related ribbon-like subcortical heterotopia is characterized by ribbon-like subcortical heterotopia, and may also include polymicrogyria, hydrocephalus, developmental delay, and intellectual disability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in inheritance pattern or phenotypic variability between band heterotopia (MIM:600348) and hydrocephalus (no MIM). Therefore, the following disease entities have been lumped into one disease entity, EML1-related ribbon-like subcortical heterotopia.
Four missense, two nonsense, and one large deletion variants that have been reported in six probands in four publications (PMIDs: 24859200, 28556411, 31710781, 34211111) are included in this curation. The mechanism of pathogenicity is unknown at this time. This gene-disease relationship is also supported by expression studies, a mouse model, rescue studies, protein-protein interactions, and functional alteration in patient cells (PMIDs: 24859200, 31390572, 34211111). In summary, there is definitive evidence supporting the relationship between EML1 and autosomal recessive EML1-related ribbon-like subcortical heterotopia. 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 Brain Malformations GCEP on the meeting date May 27th, 2025 (SOP Version 11).
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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