Resolving SLC6A1 variable expressivity with deep clinical phenotyping and Drosophila models

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.

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Publication Details

Journal
Human Genetics and Genomics Advances
Published
2025-10-31
DOI
https://doi.org/10.1016/j.xhgg.2025.100541
Primary Topic
Genomics and Rare Diseases
Type
article
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article

Resolving SLC6A1 variable expressivity with deep clinical phenotyping and Drosophila models

Oguz Kanca, Jennifer E. Posey, Kelvin Pham, Joy D. Cogan et al.
Human Genetics and Genomics Advances
Genomics and Rare Diseases
article

Resolving SLC6A1 variable expressivity with deep clinical phenotyping and Drosophila models

Oguz Kanca, Jennifer E. Posey, Kelvin Pham, Joy D. Cogan, Nikhita Gogate, Kimberly Ezell, Sumit Pruthi, Jonathan C. Andrews, Hugo J. Bellen, Herman A. Dierick, Sharayu V. Jangam, John A. Phillips, Ryan J. German, Kyong‐Mi Chang, Thomas A. Cassini, Shinya Yamamoto, Lynette Rives, Kristy L. Jay, Vanessa Gómez‐Vallejo, Eric A. Storch, Michael F. Wangler, Emily Jellinek-Russo, Rizwan Hamid, Hongling Pan, Paige I. Hall
article en

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.

Human Genetics and Genomics AdvancesVol. 7(1)
Baylor College of Medicine (US), Neurological Research Institute (US), Texas Children's Hospital (US), Baylor Genetics (US), University of Houston (US), Vanderbilt University Medical Center (US)
Openalex Percentile: Top 66%
Genomics and Rare Diseases
DOIOpen Access PDFOpenAlex
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