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Intellectual disability

Gene: GOT2

Amber List (moderate evidence)

GOT2 (glutamic-oxaloacetic transaminase 2)
EnsemblGeneIds (GRCh38): ENSG00000125166
EnsemblGeneIds (GRCh37): ENSG00000125166
OMIM: 138150, Gene2Phenotype
GOT2 is in 3 panels

3 reviews

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Four individuals from three unrelated families reported, EE/DD phenotype.
Created: 6 Feb 2020, 8:38 p.m. | Last Modified: 6 Feb 2020, 8:38 p.m.
Panel Version: 3.0

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 82, MIM# 618721

Publications

Variants in this GENE are reported as part of current diagnostic practice

Catherine Snow (Genomics England)

I don't know

Konstantinos Varvagiannis reviewed van Karnebeek et al. (2019 - PMID: 31422819) who identified four children from three families who have pathogenic variants in GOT2. Trio analysis was performed on the first family which identified a compound hetrozygous variant p.Leu209del p.Arg337Gly in the proband. WES was performed on affected probands of families II and III. Missense variants in family 2 p.Arg262Gly and p.Gly366Val in family 3 were identified. Seizures occurred in all affected individuals and began from 4 months - 9 months, failure to thrive/feeding difficulties and postnatal microcephaly was observed prior to the onset of seizures in all individuals. A number of functional studies have been performed to provide evidence for GOT2 as evidence for the individuals phenotypes and metabolic defects. GOT2 is currently not associated with any phenotypes in OMIM and Gene2Phenotype. Administration of serine and pyridoxine led to clinical improvement (cessation / better control of seizures) in family 1 and family 3, (2 individuals) therefore treatable tag has been added. Serine supplementation could not be started in family 2 (2 individuals). Classifying as Amber as limited pedigree information and awaiting further literature support.
Created: 28 Aug 2019, 4:06 p.m. | Last Modified: 28 Aug 2019, 4:06 p.m.
Panel Version: 2.1017

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Intellectual disability; Seizures

Publications

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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
Created: 25 Aug 2019, 7:54 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Seizures
  • Increased serum lactate
  • Hyperammonemia
  • Microcephaly
  • Failure to thrive
  • Feeding difficulties
  • Abnormality of nervous system morphology
Tags
treatable watchlist
OMIM
138150
Clinvar variants
Variants in GOT2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

28 Aug 2019, Gel status: 2

Added Tag, Added Tag

Catherine Snow (Genomics England)

Tag treatable tag was added to gene: GOT2. Tag watchlist tag was added to gene: GOT2.

28 Aug 2019, Gel status: 2

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: got2 has been classified as Amber List (Moderate Evidence).

25 Aug 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: GOT2 was added gene: GOT2 was added to Intellectual disability. 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