GLS was first reported in relation to autosomal recessive glutaminase deficiency in 2018 (Lynch DS, et al., 2018, PMID: 29468182). Glutaminase deficiency is characterized by refractory seizures, respiratory failure, brain abnormalities and death in the neonatal period, though milder cases with spastic ataxia-dysarthria have also been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Five unique variants (nonsense, frameshift, and missense) have been reported as well as a 5’ UTR repeat expansion (normally occurring in 8 or 16 repeats) ranging from 680 to 1500 repeats. Variants in this gene have been reported in six probands in 3 publications (PMIDs: 29468182, 30575854, 30970188), and segregated with disease in at least 2 additional family member. Experimentally, this gene-disease relationship is supported by its role in the production of glutamate, the main excitatory neurotransmitter in the central nervous system, including the brain stem respiratory center (PMID: 12963351) and a mouse model with partial recapitulation of disease (PMID: 16641247). In summary GLS is definitively associated with autosomal recessive glutaminase deficiency.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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