SLC6A9

Molecular Characteristics

To date, only ten individuals with GLYT1 encephalopathy from five unrelated families have been described in the literature, all of them harboring genetic variants in SLC6A9. In all cases, parents were consanguineous, and an autosomal recessive inheritance was observed. Three families presented truncating variants: p.(Lys310Phefs*31), p.(Gln573*) and p.(Arg333Alafs*3); and two families had missense variants: p.(Ser407Gly) and p.(Val118Met).

The pathophysiologic mechanism of the disorder is loss of the transporter function (or a severely diminished activity), which leads to high levels of extracellular glycine in the synaptic clefts, resulting in overactivation of both glycine receptors and NMDA receptors.

The diagnosis of GLYT1 encephalopathy is established in a proband by identification of biallelic pathogenic variants in SLC6A9 by molecular genetic testing. The genetic testing approaches to be considered include single-gene testing (if GLYT1 encephalopathy is clearly suspected), a multigene panel including all genes related to glycine encephalopathies (if a glycine encephalopathy is suspected in general) or whole-exome sequencing (when there is no clear clinical diagnosis). Of note, genetic variants in regulatory regions will not be detected by any of these methods, and single-gene testing by Sanger sequencing does not allow the detection of large deletions or duplications. Although to date these types of variants have not been described for GLYT1 encephalopathy, they are a potential cause of the disease. If the clinical diagnosis is clear and the results of genetic testing are negative, whole-genome sequencing should be considered.