Submission Details

The SLC18A2 gene, coding for the vesicular monoamine transporter 2 (VMAT2), plays a crucial role in transporting monoamine neurotransmitters into synaptic vesicles. SLC18A2 was first reported in relation to autosomal recessive brain dopamine-serotonin vesicular transport disease in 2013 (Rilstone et al., PMID: 23363473). The affected individuals typically present global developmental delay and cognitive impairment, hypotonia, dystonia and Parkinsonism, oculogyric crisis, temperature dysregulation, excessive sweating, hypersalivation, and gastrointestinal dysmotility with inter- and intra-familial variability. Twenty-two unique variants, including missense, nonsense, and frameshift variants, have been reported in 25 affected individuals in 9 publications (PMIDs: 23363473, 31240161, 28716265, 26497564, 29450879, 26539891, 36318270, 31618753, 3871642) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease association is also supported by experimental evidence. Overexpression of SLC18A2 Pro387Leu mutant in COS-7 cells dramatically decreased monoamine uptake without affecting protein glycosylation (PMID: 23363473). Platelets derived from the patient with SLC18A2 Pro316Ala alteration showed significantly lower serotonin levels, abnormal morphology, and reduced aggregation response in comparison to the heterozygous carriers and controls (PMID: 31240161). Homozygous knockout (KO) mice exhibited various symptoms including small size, poor suckling, hypoactivity, motor coordination issues, and neonatal death (PMID: 9427250, 9427251, 11463816). Additionally, a transgenic mouse line expressing ~5% normal VMAT2 levels [low expressor VMAT2 LO] led to age-dependent reduction in dopamine content and uptake in brain, abnormal locomotor skills and neuronal degeneration similar to Parkinson disease (PMID: 17652604). These features are consistent with the symptoms presented by patients harboring SLC18A2 variants. SLC18A2-overexpressing mice using a bacterial artificial chromosome (BAC) showed increased vesicular volume, dopamine uptake, content and release, along with increased locomotor activity, and reduced anxiety/depressive behavior (PMID: 24979780). In summary, SLC18A2 is definitively associated with autosomal recessive brain dopamine-serotonin vesicular transport disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen IEM GCEP on the meeting date July 26, 2024] (SOP Version 10).