Submission Details

The relationship between SLC6A8 and X-linked creatine transporter deficiency was evaluated using the ClinGen Clinical Validity Framework as of December 12, 2019. Variants in SLC6A8, which encodes the creatine transporter (CT1, CRTR, CRT) were first reported in individuals with cerebral creatine deficiency in 2001 (Salomons et al, PMID: 11326334). Clinical symptoms in affected males include intellectual disability with little or no speech, seizures, autistic behaviors, and movement disorder. Heterozygous females have highly variable presentation ranging from no clinical symptoms, to mild language disability, to seizures and intellectual disability. Proton magnetic resonance spectroscopy reveals reduced or absent creatine in the brain. In affected males, urine creatine is markedly elevated but it can be normal in heterozygous females. Data from 11 probands (9 male, 2 female) with 11 unique variants (missense, nonsense, frameshift, splice site) were curated from 10 publications (Salomons et al, 2001, PMID 11326334; Hahn et al, 2002, PMID 11898126; Rosenberg et al, 2004, PMID 15154114; Shiaffino et al, 2005, PMID 16086185; Póo-Argüelles et al, 2006, PMID 16601898; Battini et al, 2007, PMID 17603797; Anselm et al, 2008, PMID 18443316; Fons et al, 2009, PMID 19706062; Mercimek-Mahmutoglu et al, 2010, PMID 20846889; Betsalel et al, 2011, PMID 20717164). Segregation was demonstrated in one curated family, with a LOD score of 2.4 (Hahn et al, 2002, PMID 11898126). More case-level information is available in the published literature but the maximum score for genetic evidence (12 points has been reached). This gene disease relationship is supported by the biochemical function of the creatine transporter which is consistent with the finding of cerebral creatine deficiency in patients (Guimbal et al, 1993, PMID 8473283; Braissant et al, 2010, PMID 19879361); the knowledge that variants in genes involved in creatine synthesis (GATM, which encodes arginine-glycine amidinotransferase, and GAMT, which encodes guanidinoacetate methyltransferase) are definitively associated with cerebral creatine deficiency and result in similar symptoms to SLC6A8 deficiency (Boorsook et al, 1940, PMID 17789505; Cantoni et al, 1954, PMID 13192118); rescue of creatine transport in SLC6A8-deficient fibroblasts by SLC6A8 cDNA (Rosenberg et al, 2006, PMID 16763899) and failure of missense variants to correct creatine transport ability of SLC6A8-deficient cells (Betsalel et al, 2012, PMID 20717164); and the clinical and biochemical symptoms in ubiquitous and brain-specific mouse models (Skelton et al, 2011, PMID 21249153; Baroncelli et al, 2014, PMID 25485098; Kurosawa et al, 2012, PMID 22751104). More experimental evidence to support this gene-disease relationship is available in the published literature but the maximum score for experimental evidence (6 points) has been reached. In summary, SLC6A8 is definitively associated with creatine transporter deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.