Intellectual disability - microarray and sequencing
Gene: GOT2Comment on list classification: ID of relevant severity to this panel (severe-to-profound) is reported in 4/4 individuals (PMID:31422819). However, intellectual impairment was secondary to epilepsy and there is no evidence of neurodevelopmental delay preceding the onset of seizures. Therefore, maintaining Amber rating on this panel (GOT2 is already Green on the Genetic epilepsy syndromes (v2.236) panel)Created: 18 Dec 2020, 3:01 p.m. | Last Modified: 18 Dec 2020, 3:01 p.m.
Panel Version: 3.656
GOT2 is now listed in Gene2Phenotype with a 'probable' disease confidence rating for 'Malate-Aspartate Shuttle-Related Encephalopathy', and is also associated with 'Epileptic encephalopathy, early infantile, 82, MIM# 618721' in OMIM.Created: 18 Dec 2020, 2:51 p.m. | Last Modified: 18 Dec 2020, 2:51 p.m.
Panel Version: 3.655
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
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
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: LiteratureCreated: 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
Tag watchlist was removed from gene: GOT2.
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
Gene: got2 has been classified as Amber List (Moderate Evidence).
Tag treatable tag was added to gene: GOT2. Tag watchlist tag was added to gene: GOT2.
Gene: got2 has been classified as Amber List (Moderate Evidence).
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