Resolving SLC6A1 variable expressivity with deep clinical phenotyping and Drosophila models
Year: 2025
Type: article
Abstract: Variants in SLC6A1 result in a rare neurodevelopmental disorder characterized by a variable clinical presentation of symptoms including developmental delay, epilepsy, motor dysfunction, and autism spectrum disorder. SLC6A1 haploinsufficiency has been confirmed as the predominant pathway of SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD); however, the molecular mechanism underlying the variable clinical presentation remains unclear. Here, through work of the Undiagnosed Diseases Network, we identify an individual with an inherited p.A334S variant of uncertain significance. To resolve this variant and better understand the variable expressivity associated with SLC6A1, we assess the phenotypes of the proband in comparison with a cohort of 13 individuals diagnosed with SLC6A1-NDD. We then create an allelic series in Drosophila melanogaster to functionally characterize these variants. Informatic clustering based on these clinical findings points to significant clinical overlap between the unsolved individual and confirmed SLC6A1-NDD. We confirm phenotypes in flies expressing SLC6A1 variants consistent with a partial loss-of-function mechanism. We conclude that the p.A334S variant is a hypomorphic allele and begin to elucidate the underlying variability in SLC6A1-NDD. These insights will inform clinical diagnosis, prognosis, intervention, and inform therapeutic design for those living with SLC6A1-NDD.
Authors: Kristy L. Jay, Nikhita Gogate, Paige I. Hall, Kimberly M. Ezell, Jonathan C. Andrews, Sharayu V. Jangam, Hongling Pan, Kelvin Pham, Ryan German, Vanessa Gomez, Emily Jellinek-Russo, Eric A. Storch, Shinya Yamamoto, Oguz Kanca, Hugo J. Bellen, Herman A. Dierick, Joy D. Cogan, John A. Phillips, Rizwan Hamid, Thomas Cassini, Lynette Rives, Sumit Pruthi, Hua-Chang Chen, Jennifer E. Posey, Michael F. Wangler
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,300
Funders: Vanderbilt University, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Common Fund
Awards: Baylor Intellectual and Developmental Disabilities Research Centers, Overall: Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Center at Vanderbilt, Center for functional analysis of human UDN gene homologs in Drosophila and zebrafish, Vanderbilt Center for Undiagnosed Diseases (VCUD), Baylor College of Medicine Intellectual and Developmental Disabilities Research Center, C BRIGGSAE AND C ELEGANS GENOMIC SEQUENCE COMPARISON, Harnessing Clinical Genomic Characterization to Accelerate Translational Advances for Patients with IDD, G8177651809, Broad-Geisinger Clinical Genome Resource, Neuronal Mechanisms of Metabolic and Genetic Defects of the Peroxisome, Diagnosing the Unknown for Care and Advancing Science (DUCAS)
OpenAlex ID: W4415752566