De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia

Since 2016, variants in SLC12A2 have been implicated in human disease, with several different phenotypes being linked to the gene. The first report concerned a child with a complex syndrome marked by metabolic derangement but normal hearing and cognition and a de novo heterozygous loss of function variant. Subsequently, several patients with severe developmental delay, sensorineural hearing loss, and bi-allelic loss of function variants were reported; this condition is known as Kilquist syndrome. The SLC12A2 knockout mouse model has a phenotype that is quite similar to Kilquist patients. In 2020, heterozygous variants in SLC12A2 were identified as a cause of non-syndromic deafness associated with vestibular areflexia (DFNA78; MIM 619081). In addition, de novo heterozygous SLC12A2 variants have also been implicated in developmental delay with autistic features. SLC12A2 encodes a Na+K+2Cl- cotransporter (NKCC) that is widely expressed in neurons, glial cells, the trachea, salivary glands, intestine, sweat glands, and the cochlea. In the inner ear, K+ transport is required for the mechano-transduction of auditory stimuli. SLC12A2 functions as a dimer and has several isoforms; only one isoform contains exon 21, and this isoform is almost exclusively expressed in the inner ear/cochlea. This isoform is necessary for homeostasis of the endolymph. To date, the published pathogenic variants causing DFNA78 are missense mutations located within exon 21 or in the 3' splice site of exon 21. We report a patient with profound congenital hearing loss and vestibular areflexia with a de novo variant in SLC12A2 located in the splice donor site: NM_001046.2: c.2977+4_2977+7del causing an in-frame skip of exon 21, as shown by cDNA analysis. Our case adds to the evidence that loss of exon 21 of SLC12A2 leads to a cochlear restricted phenotype. From a genetic counseling point of view, it reminds us that beyond syndromic forms such as Usher syndrome, several non-syndromic forms of genetically determined sensorineural hearing loss, including those involving the SLC12A2 gene, may also present with vestibular areflexia. This underscores the need for a broad sequencing approach when faced with this clinical scenario.