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Early onset or syndromic epilepsy v2.237 GOT2 Arina Puzriakova Phenotypes for gene: GOT2 were changed from Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology to Epileptic encephalopathy, early infantile, 82, OMIM:618721; Developmental and epileptic encephalopathy, 82, MONDO:0032880
Early onset or syndromic epilepsy v2.0 GOT2 Louise Daugherty commented on gene: GOT2
Early onset or syndromic epilepsy v2.0 GOT2 Louise Daugherty Tag watchlist was removed from gene: GOT2.
Early onset or syndromic epilepsy v1.431 GOT2 Rebecca Foulger Classified gene: GOT2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.431 GOT2 Rebecca Foulger Gene: got2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.430 GOT2 Rebecca Foulger commented on gene: GOT2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.405 GOT2 Rebecca Foulger commented on gene: GOT2
Early onset or syndromic epilepsy v1.336 GOT2 Helen Lord reviewed gene: GOT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.259 GOT2 Catherine Snow Tag treatable tag was added to gene: GOT2.
Tag watchlist tag was added to gene: GOT2.
Early onset or syndromic epilepsy v1.259 GOT2 Catherine Snow Classified gene: GOT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.259 GOT2 Catherine Snow Gene: got2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.258 GOT2 Catherine Snow reviewed gene: GOT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.256 GOT2 Konstantinos Varvagiannis gene: GOT2 was added
gene: GOT2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GOT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOT2 were set to 31422819
Phenotypes for gene: GOT2 were set to Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology
Penetrance for gene: GOT2 were set to Complete
Review for gene: GOT2 was set to GREEN
Added comment: van Karnebeek et al. (2019 - PMID: 31422819) report on 4 individuals from 3 families, with biallelic GOT2 pathogenic variants (3 missense SNVs and 1 in-frame deletion).

The phenotype corresponded to a metabolic encephalopathy with onset of epilepsy in the first year of life (4/4) with DD and ID (4/4). Additional features included postnatal microcephaly, failure to thrive/feeding difficulties and cerebral anomalies (atrophy and white matter). All subjects had high blood lactate and hyperammonemia. Plasma serine was low in one case (alternative causes were ruled out).

Administration of serine and pyridoxine led to clinical improvement (cessation / better control of seizures) in 2 subjects suggesting that GOT2 deficiency may be amenable to therapeutic intervention. [Treatment could not be started in the 2 further affected individuals].

GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase, a component of the malate-aspartate shuttle (MAS). The latter is important for intracellular NAD(H) redox homeostasis.

The authors provide several lines of evidence that GOT2 deficiency explains the patients' phenotype and metabolic defects incl. :
- Reduced GOT2 protein levels (due to lower expression/impaired stability) and diminished activity in patient fibroblasts (lower activity was also shown for carriers). Rescue of the GOT enzymatic activity was observed upon transduction of patient fibroblasts using lentiviral particles with wt GOT2.
- Impairment of de novo serine biosynthesis in patient (and to a lesser extent in carrier) fibroblasts compared to controls. This was similar in GOT2-knockout HEK293 cells. Serine biosynthesis in these cells was restored by pyruvate supplementation.
- CRISPR/Cas9 Got2-knockout mice resulted in early lethality (during pregnancy). Heterozygous mice were viable and healthy.
- Morpholino knockdown of got2a in zebrafish was shown to perturb embryonic development (smaller head, slow circulation, bend body, brain developmental defects, etc). Pyridoxine and serine in embryo water resulted in milder phenotypes/improved morphant survival. Zebrafish got2a morphants had seizure-like spikes upon EEG that were rescued by treatment with pyridoxine.

GOT2 is not associated with any phenotype in OMIM/G2P.

As a result, this gene can be considered for inclusion in both epilepsy and ID gene panels probably as green (3 families, relevant phenotypes and severity, evidence from cell and animal studies) or amber.

[Please consider inclusion in other relevant panels eg. mitochondrial disorders, metabolic disorders and/or addition of the 'treatable' tag].
Sources: Literature