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Eukaryotic translation elongation factor 2 (eEF2) is a GTP-dependent translocase that catalyzes ribosomal translocation during protein synthesis and is encoded by EEF2 (HGNC:3214) (Gene Symbol). Heterozygous missense variants in EEF2 were previously linked to adult-onset spinocerebellar ataxia type 26. Recent evidence expands the phenotypic spectrum to include a childhood-onset neurodevelopmental disorder with benign external hydrocephalus (MONDO:0700092) (Disease Name).
Clinical exome sequencing in three unrelated children presenting with motor delay and relative macrocephaly with ventriculomegaly identified de novo heterozygous missense variants in EEF2: c.463C>A (p.Leu155Met) and c.1359G>A (p.Met453Ile) (PMID:33355653). These variants are absent from population databases, consistent with a dominant de novo mechanism. No additional familial segregation has been observed.
The identified variants localize to conserved regions of eEF2 critical for GTP binding and conformational dynamics. Both c.463C>A (p.Leu155Met) and c.1359G>A (p.Met453Ile) affect amino acids conserved across eukaryotes and are predicted deleterious by multiple in silico tools. No recurrent or founder alleles have been reported in this neurodevelopmental context.
Functional complementation studies in Saccharomyces cerevisiae demonstrated that patient-derived variants impair cellular growth, increase sensitivity to translation inhibitors, and reduce translational fidelity, mirroring loss of normal elongation activity (PMID:33355653). These findings align with eEF2’s established role in maintaining translational accuracy and proteostasis.
Collectively, three de novo occurrences with concordant functional deficits support a dominant-negative or neomorphic mechanism. The integration of genetic and experimental data meets moderate ClinGen criteria for gene–disease validity.
In summary, EEF2 should be included in diagnostic panels for early-onset motor delay and ventriculomegaly; molecular diagnosis informs prognosis and genetic counseling.
Gene–Disease AssociationModerateThree unrelated de novo probands with concordant functional yeast model data supporting pathogenicity ([PMID:33355653]). Genetic EvidenceModerateThree de novo missense variants in unrelated individuals absent from population databases; consistent with dominant de novo inheritance ([PMID:33355653]). Functional EvidenceModerateYeast complementation assays demonstrate patient-derived variants impair growth, translation inhibitor sensitivity, and translational fidelity in line with human phenotype ([PMID:33355653]). |