SLC6A9

Inheritance Pattern: AR

Disease ID:MONDO:0015010

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: Unknown

Disease ID:MONDO:0015010

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0015010

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0015010

Submitter: ClinGen

The gene *SLC6A9* was first reported in relation to autosomal recessive atypical glycine encephalopathy in 2016 (Kurolap et al., PMID: 27773429). *SLC6A9* encodes the glycine transporter GLYT1, which is predominantly expressed in astrocytes and is essential for clearing glycine from the extracellular space, thereby terminating glycinergic neurotransmission. This function is critical for maintaining inhibitory signaling in the central nervous system. Atypical glycine encephalopathy, also known as GLYT1 encephalopathy (OMIM #617301), is a rare neonatal-onset disorder characterized by severe hypotonia, respiratory failure, arthrogryposis multiplex congenita, dysmorphic facial features, and abnormal brain MRI findings. Despite normal or only mildly elevated serum glycine levels, cerebrospinal fluid (CSF) glycine is consistently elevated. Most patients die in infancy. This gene-disease relationship is supported by genetic evidence from six probands across five publications. These include four individuals with predicted or proven null variants (PMIDs: 27773429, 33269555), and two individuals with missense variants (PMIDs: 27481395, 32712301, 36195292). Functional studies in recombinant systems demonstrated that *SLC6A9* variants resulted in severely diminished or absent transport activity (PMID: 32712301). All probands presented with consistent phenotypes and were homozygous due to consanguinity. The total genetic evidence score was 6.6 points. Segregation data from two families contributed an additional 1.2 points (PMIDs: 27773429, 36195292). Experimental evidence further supports this gene-disease relationship. Expression studies confirmed that GLYT1 is highly expressed in the brainstem and spinal cord, consistent with the neurological phenotype (PMID: 27773429). Biochemical function studies established that GLYT1 is a sodium- and chloride-dependent glycine transporter essential for regulating glycine levels at inhibitory synapses (PMID: 8183239). Non-human model organisms, including Slc6a9-null mice and zebrafish, recapitulated key features of the human phenotype. Slc6a9-null mice exhibited lethargy, hypotonia, respiratory failure, and early death (PMID: 14622582), while slc6a9 mutant zebrafish showed neuromuscular abnormalities such as reduced spontaneous coiling and absent swimming behavior (PMID: 16014722). Additional mouse models with conditional GlyT1 deletion confirmed elevated CSF glycine and neurological symptoms (PMID: 27773429). The total experimental evidence score was 5.5 points. In summary, there is Definitive evidence to support the relationship between *SLC6A9* and autosomal recessive atypical glycine encephalopathy, demonstrated through robust genetic and experimental data, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on July 25, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0015010

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0017354

Submitter: Orphanet