SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect

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.

A Drosophila screen identifies NKCC1 as a modifier of NGLY1 deficiency

“…The NKCC1-deficient patient also had severe hearing loss, cochlear defects, and abnormal auditory brainstem responses (ABRs). Several patients with missense mutations in NKCC1, rather than complete loss-of-function mutations, display bilateral sensorineural hearing loss ( McNeill et al, 2020 ). NGLY1 deficiency patients do not have severe hearing loss, but do report abnormal ABRs.…”

Sodium Transporters in Human Health and Disease

“…Because her fibroblasts were collected, genetic analysis revealed that she carried both her parent's mutations. Evidence is now mounting that de novo (single allele) mutations lead to neurodevelopmental deficits and cochlea-vestibular defects (McNeill et al, 2020;Mutai et al, 2020). Another patient with NKCC1 mutation deserves some attention in the context of this review article.…”

NKCC1: Newly Found as a Human Disease-Causing Ion Transporter

“…In a second study, we identified three individuals from two independent families with mutations in exon 21 associated with nonsyndromic bilateral sensorineural deafness ( Table 2 ). 99 In the first family, a 2-year-old boy had a p.Glu980Lys mutation, and in the second family, a 44-year-old father and his 5-year-old son carried a mutation of the preceding residue (p.Glu979Lys). Note that two additional patients with mutations in other parts of the transporter (p.Ala327Val and p.Trp892*) also demonstrated bilateral sensorineural hearing impairment.…”

“…Note that two additional patients with mutations in other parts of the transporter (p.Ala327Val and p.Trp892*) also demonstrated bilateral sensorineural hearing impairment. 99 …”