Jenny Goldstein: “Annual update on the NIH-funded ClinGen Cerebral Creatine Deficiency Syndrome Variant Curation Expert Panel”
ABSTRACT
Understanding the clinical significance of variants within the genes causing cerebral creatine deficiency syndromes (CCDS) is important to ensure timely diagnosis and initiation of treatment for these disorders. In 2022, the NIH-funded ClinGen CCDS Variant Curation Expert Panel (VCEP) developed guidelines to classify the clinical significance of variants in GATM, GAMT, and SLC6A8. To date, the ClinGen CCDS VCEP has classified 55 variants in GATM, 121 variants in GAMT, and 171 variants in SLC6A8. Variant classifications are submitted quarterly to ClinVar, a public variant database. The guidelines and classifications can help genetic testing laboratories to provide accurate information to families, inform studies on the prevalence of these disorders, and contribute to the overall understanding of the genetic causes of the CCDS. We will discuss the current status of the ClinGen CCDS VCEP including 1) the impact of the CCDS VCEP’s updated guidance for the classification of variants in SLC6A8 which, among other updates, allows for increased sensitivity and scoring for phenotype specificity that can be observed in females with creatine transporter deficiency (CTD), and 2) our collaboration with the ACD’s patient registry, CreatineINFO, to obtain biochemical and genetic data that is critical for the VCEP to accurately assess the clinical impact of variants in genes causing CCDS. Collaboration between the ACD and ClinGen increases understanding of the clinical significance of variants in the genes causing CCDS and may serve as a model for collaboration between other ClinGen VCEPs and patient advocacy organizations.