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Early onset or syndromic epilepsy v2.499 EEF1A2 Sarah Leigh Mode of pathogenicity for gene: EEF1A2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v2.491 EEF1A2 Sarah Leigh Tag for-review was removed from gene: EEF1A2.
Early onset or syndromic epilepsy v2.491 EEF1A2 Sarah Leigh commented on gene: EEF1A2: NHS Genomic Medicine Service consideration - the phenotype is appropriate for this panel
Early onset or syndromic epilepsy v2.491 EEF1A2 Sarah Leigh commented on gene: EEF1A2: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams changed review comment from: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1AS null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.; to: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams Tag for-review tag was added to gene: EEF1A2.
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams edited their review of gene: EEF1A2: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 32160274
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams commented on gene: EEF1A2
Early onset or syndromic epilepsy v1.191 EEF1A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EEF1A2.
Early onset or syndromic epilepsy v1.190 EEF1A2 Rebecca Foulger Source NHS GMS was added to EEF1A2.
Early onset or syndromic epilepsy v1.189 EEF1A2 Rebecca Foulger reviewed gene: EEF1A2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 EEF1A2 Tracy Lester reviewed gene: EEF1A2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27441201, 28378778 ; Phenotypes: Epileptic encephalopathy, early infantile, 616409, Mental retardation , 616393; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.13 DHPS Konstantinos Varvagiannis gene: DHPS was added
gene: DHPS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DHPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHPS were set to 21389784; 21850436
Phenotypes for gene: DHPS were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; EEG abnormality; Behavioral abnormality; Abnormality of head or neck
Penetrance for gene: DHPS were set to Complete
Review for gene: DHPS was set to GREEN
Added comment: Ganapathi et al. (doi.org/10.1016/j.ajhg.2018.12.017 - PMID : NA) report on 5 individuals from 4 unrelated families with biallelic pathogenic variants in DHPS.

The phenotype consisted of DD/ID (5/5), tone abnormalities (hypotonia/hypertonia/spasticity - 5/5), seizures (5/5 - in one case though unclear staring spells) with EEG abnormalities (5/5). Additionally most individuals displayed behavioral issues, or some common facial features.

Several other disorders had been ruled prior to the diagnosis, in all cases by exome sequencing.

All individuals harbored a specific missense variant (c.518A>G or p.Asn173Ser) in trans with various other variants incl. a splice site mutation (c.1014+1G>A), an in-frame deletion of 2 amino acids (c.912_917delTTACAT or p.Tyr305_Ile306del) or a variant abolishing the translation initiation codon (c.1A>G or p.Met1?) [All variants using NM_001930.3 as a reference].

Deoxyhypusine synthase (encoded by DHPS) is an enzyme participating in the first step of hypusine synthesis, an amino-acid which is specific to eukaryotic initiation factor 5A (eIF5A) and its homolog (eIF5A2).

eIF5A, its hypusinated form and DHPS have all been previously implicated in cellular proliferation/differentiation. eIF5A has also been proposed to be a mRNA translation elongation factor. A role of eIF5A in neuronal growth and survival has been proposed previously (all ref. in present article).

Neither eIF5A, nor DHPS or DOHH (an enzyme required for the second step of hypusination) have been associated to any disorders previously. Mutations in genes encoding other eukaryotic elongator factors (eg. EEF1A2, EEF2) have been associated with neurodevelopmental disorders.

Concerning the DHPS variants reported:

cDNA studies suggested that the c.1014+1G>A variant is translated but results in aberrant splicing and truncation of the protein before its active site.

The in-frame deletion as well as the missense variant were shown to have absent or partial (20%) enzyme activity in vitro respectively compared to wild-type (following expression in E.coli BL21(DE3) cells).

In line with this, reduced hypusination of eIF5A was observed for these 2 variants when compared to wild-type DHPS, upon co-transfection of constructs overexpressing DHPS (wt or mut.) and eIF5A in HEK293T cells.

Absence of homozygous DHPS LoF variants in population databases might suggest that complete deficiency is incompatible with normal embryonic development. Mice heterozygous for Dhps deletion do not demonstrate severe phenotypes, though homozygosity is embryonically lethal (PMIDs: 21389784, 21850436).
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DHPS is not associated with any phenotype in G2P, nor in OMIM.
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As a result, DHPS can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy EEF1A2 Sarah Leigh marked gene: EEF1A2 as ready
Early onset or syndromic epilepsy EEF1A2 Sarah Leigh classified EEF1A2 as Green List (high evidence)
Early onset or syndromic epilepsy EEF1A2 Sarah Leigh classified EEF1A2 as Green List (high evidence)
Early onset or syndromic epilepsy EEF1A2 Zornitza Stark reviewed gene: EEF1A2
Early onset or syndromic epilepsy EEF1A2 Sarah Leigh Added gene to panel