Slc26a4, encoding pendrin, is a member of the SLC26A transporter family. It transports various ions like bicarbonate, chloride, iodine, and oxalate, and is involved in maintaining hearing function, renal function, blood pressure, and hormone and pH regulation [6]. Mutations in Slc26a4 are a common cause of deafness, responsible for Pendred syndrome and non-syndromic enlarged vestibular aqueduct (EVA) [1,3,4,5].

In China, a large-scale molecular epidemiological survey of Slc26a4 in non-syndromic hearing loss patients found a high ratio of EVA in the deaf population, with distinct mutational spectra among ethnicities and regions. Most variants caused pendrin retention in the intracellular region and reduced its transport capability [1]. An experimental approach was developed to quantify the pathogenic effects of Slc26a4 disease-associated variants. Stable cell lines expressing pendrin missense variants were established, and their anion transport activities were determined, helping to distinguish functional and non-functional variants [2]. The mutant Slc26a4 phenotype is characterized by inner ear malformations, progressive and fluctuating hearing loss, and vestibular dysfunction. Pendred syndrome and non-syndromic recessive hearing loss DFNB4 are caused by biallelic mutations, while some EVA patients have only one detectable mutant allele. A haplotype called CEVA in European-Caucasian patients can act as a pathogenic recessive allele in trans to other mutations, resulting in a less severe phenotype [3].

In conclusion, Slc26a4 is crucial for normal inner ear function, and its mutations are significantly associated with hearing loss-related diseases such as Pendred syndrome and EVA. Functional studies on its variants, along with understanding its genetic architecture, contribute to genetic diagnosis, counseling, prenatal and pre-implantation diagnosis in related families.