Submission Details

GPT2 was first reported in relation to autosomal recessive glutamate pyruvate transaminase 2 deficiency in 2014 (Iglesias et al., PMID: 24901346). This neurologic syndrome is characterized by delayed psychomotor development, moderately to severely impaired intellectual development, and poor or absent speech. More severely affected individuals show poor overall growth with progressive microcephaly, axial hypotonia, oromotor dysfunction with drooling, joint contractures, and spastic paraplegia resulting in walking difficulties. Eight variants (missense, frameshift, nonsense, and splice variants) that have been reported in 7 probands (and 22 family members) in 4 publications (PMIDs: 31471722, 29882329, 25758935, and 27601654) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by its biochemical function catalyzing a reversible transamination reaction between L-alanine and 2-oxoglutarate to produce glutamate and pyruvate (PMID: 11863375), required for amino acid metabolism and neurotransmitter production. As well as its expression at increasing levels in brain during early postnatal development (PMID: 27601654) and a mouse model with decreases in postnatal brain growth and reduced alanine levels, akin to the human phenotype (PMID: 27601654). In summary, GPT2 is definitively associated with autosomal recessive glutamate pyruvate transaminase 2 deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.