McNeill, A., Iovino, E., Mansard, L. et al. (17 more authors) (2020) SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect. Brain, 143 (8). pp. 2380-2387. ISSN 0006-8950
Abstract
The SLC12 gene family consists of SLC12A1–SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16–18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16–18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 The Authors. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an author-produced version of a paper subsequently published in Brain. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Corticogenesis; neurodevelopmental disorder; de novo mutation; exome; brain |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 04 May 2020 11:24 |
Last Modified: | 19 Jan 2022 11:00 |
Status: | Published |
Publisher: | Oxford University Press (OUP) |
Refereed: | Yes |
Identification Number: | 10.1093/brain/awaa176 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:160142 |