SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect

Alisdair McNeill (Lead / Corresponding author), Emanuela Iovino, Luke Mansard, Christel Vache, David Baux, Emma Bedoukian, Helen Cox, John Dean, David Goudie, Ajith Kumar, Ruth Newbury-Ecob, Chiara Fallerini, Alessandra Renieri, Diego Lopergolo, Francesca Mari, Catherine Blanchet, Marjolaine Willems, Anne-Francoise Roux, Tommaso Pippucci, Eric Delpire (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2380-2387
Number of pages8
JournalBrain : a journal of neurology
Issue number8
Early online date13 Jul 2020
Publication statusPublished - 1 Aug 2020


  • corticogenesis
  • neurodevelopmental disorder
  • de novo mutation
  • exome
  • brain

ASJC Scopus subject areas

  • Clinical Neurology


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