SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• The SLC12 gene family encodes cation-coupled chloride co-transporters.
• SLC12A2 is implicated in corticogenesis, making it a candidate gene for neurodevelopmental disorders.

Purpose of the Study:

• To investigate the role of SLC12A2 in neurodevelopmental disorders and hearing loss.
• To identify genetic variants in SLC12A2 associated with these conditions.

Main Methods:

• Trio exome sequencing was performed on affected individuals.
• Functional assays in Xenopus laevis oocytes assessed co-transporter function.
• Analysis of SLC12A2 expression in fetal brain tissue and gene co-expression studies were conducted.

Main Results:

• De novo mutations in SLC12A2 were identified in six children with neurodevelopmental disorders, including developmental delay, intellectual disability, and sensorineural deafness.
• SLC12A2 variants were also found in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia.
• All tested variants impaired SLC12A2 co-transporter function, and high expression in fetal radial glial cells supports its role in neurogenesis.

Conclusions:

• De novo mutations in SLC12A2 cause a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss.
• SLC12A2 plays a significant role in human neurodevelopment.