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Original research
Neurodevelopmental phenotypes associated with pathogenic variants in SLC6A1
  1. Ashley Kahen1,
  2. Haluk Kavus2,
  3. Alexa Geltzeiler2,
  4. Catherine Kentros2,
  5. Cora Taylor3,
  6. Elizabeth Brooks4,
  7. LeeAnne Green Snyder4,
  8. Wendy Chung2,5
  1. 1College of Dental Medicine, Columbia University, New York, New York, USA
  2. 2Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
  3. 3Pediatric Psychology, Geisinger Autism & Developmental Medicine Institute, Lewisburg, Pennsylvania, USA
  4. 4Simons Foundation Autism Research Initiative, New York, New York, USA
  5. 5Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
  1. Correspondence to Dr Wendy Chung, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA; wkc15{at}cumc.columbia.edu

Abstract

Background SLC6A1 encodes GAT-1, a major gamma-aminobutyric acid (GABA) transporter in the brain. GAT-1 maintains neurotransmitter homeostasis by removing excess GABA from the synaptic cleft. Pathogenic variants in SLC6A1 disrupt the reuptake of GABA and are associated with a neurobehavioural phenotype.

Methods Medical history interviews, seizure surveys, Vineland Adaptive Behavior Scales Second Edition and other behavioural surveys were completed by primary care givers of 28 participants in Simons Searchlight. All participants underwent clinical whole exome sequencing or gene panel sequencing. Additional cases from the medical literature with comparable data were included.

Results We identified 28 individuals with largely de novo pathogenic/likely pathogenic variants including missense (15/21 or 71%) and truncating variants (6/21 or 29%). Missense variants were largely clustered around the sixth and seventh transmembrane domains, which functions as a GABA binding pocket. The phenotype of individuals with pathogenic variants in SLC6A1 includes hypotonia, intellectual disability/developmental delay, language disorder/speech delay, autism spectrum disorder, sleep issues and seizures.

Conclusion Pathogenic variants in SLC6A1 are associated with a clinical phenotype of developmental delay, behaviour problems and seizures. Understanding of the genotype–phenotype correlation within SLC6A1 may provide opportunities to develop new treatments for GABA-related conditions.

  • epilepsy
  • genetics
  • pediatrics

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. Our research is based on deidentified participant data from the Simons Searchlight. All data relevant to the study are included in the article or uploaded as online supplemental information and can be obtained on request (https://base.sfari.org). Reuse of the data is permitted on submission of a data request.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. Our research is based on deidentified participant data from the Simons Searchlight. All data relevant to the study are included in the article or uploaded as online supplemental information and can be obtained on request (https://base.sfari.org). Reuse of the data is permitted on submission of a data request.

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Footnotes

  • Contributors AK analysed the data and drafted and critically reviewed the manuscript. HK analysed the data and drafted and critically reviewed the manuscript. AG, CK, CT, EB and LGS provided input to the study design and critically reviewed the manuscript. WKC conceived of the study, provided clinical data, analysed the data, drafted and critically reviewed the manuscript.

  • Funding This project was supported by the National Institute of Health T35 training grant (T35HL007616) to AK. In addition, this project was supported by grants to WKC from SFARI and the JPB Foundation.

  • Competing interests CT is an employee of Geisinger Health System. EB and LGS are employees of Simons Foundation Autism Research Initiative.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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