Abstract
Intellectual disability is genetically heterogeneous, and it is likely that many of the responsible genes have not yet been identified. We describe three siblings with isolated, severe developmental encephalopathy. After extensive uninformative genetic and metabolic testing, whole exome sequencing identified a homozygous novel variant in glutamic pyruvate transaminase 2 (
GPT2
) or alanine transaminase 2 (
ALT2
), c.459 C>G p.Ser153Arg that segregated with developmental encephalopathy in the family. This variant was predicted to be damaging by all in silico prediction algorithms.
GPT2
is the gene encoding
ALT2
which is responsible for the reversible transamination of alanine and 2-oxoglutarate to form pyruvate and glutamate.
GPT2
is expressed in brain and is in the pathway to generate glutamate, an excitatory neurotransmitter. Functional assays of recombinant wild-type and mutant
ALT2
proteins demonstrated the p.Ser153Arg mutation resulted in a severe loss of enzymatic function. We suggest that recessively inherited loss of function
GPT2
mutations are a novel cause of intellectual disability.
