Submission Details

EEF1A2 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2012 (de Ligt et al., 2012; PMID: 23033978). At least 17 unique variants (missense) have been reported in at least 28 humans (reviewed in Cao et al., 2017 PMID: 28911200; and Lam et al., 2016 PMID: 27441201).Most of these cases are asserted to have occurred de novo. A website dedicated to EEF1A2 and epilepsy maintained by the Cathy Abbot Lab (IGMM, University of Edinburgh) outlines variants of interest, patients numbers, and references (https://eef1a2epilepsy.wordpress.com/). Evidence supporting this gene-disease relationship includes case-level and experimental data. More evidence is available in the literature, however the maximum score for genetic evidence (12 points) has been reached. The mechanism for the disease is presumed loss of protein function (Cao et al., 2017 PMID: 28911200). EEF1A2 has been associated with the following disease entities in the literature or nosological or ontological sites: (1) Epileptic encephalopathy, early infantile, 33 (EIEE33; MIM: 616409); (2) Mental retardation, autosomal dominant 38 (MR38; MIM: 616393); (3) Cardiac, intellectual disability, epilepsy syndrome autosomal recessive inheritance (Cao et al., 2017 PMID: 28911200). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group we found no difference in the molecular mechanism, phenotypic expressivity, or inheritance pattern between the Epileptic encephalopathy, early infantile, 33 (MIM: 616409) and Mental retardation, autosomal dominant 38 (MIM: 616393) and have lumped these disease entities into the broader entity of complex neurodevelopmental disorder. However, per the lumping and splitting criteria we found differences in the phenotypic expressivity and inheritance pattern in for cardiac, intellectual disability, epilepsy syndrome (Cao et al., 2017 PMID: 28911200) compared to the EIEE33 and MR38, therefore this gene-disease relationship represents a separate, independent curation and is not currently represented in this gene-disease classification. In summary, EEF1A2 is definitively associated with 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 classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on March 19, 2019 (SOP version 6).