Pendred Syndrome and Nonsyndromic Hearing Loss Associated with Enlarged Vestibular Aqueduct via the KCNJ10 Gene

Pendred syndrome is a congenital or prelingual sensorineural hearing impairment disorder that generally causes severe to profound hearing loss and other findings. Clinical features, in addition to hearing loss, can include an enlarged vestibular aqueduct (EVA), temporal bone abnormalities, and development of euthyroid goiter in late childhood to early adulthood (Smith. 2017. PubMed ID: 20301640). Individuals with Pendred syndrome who have EVA can also have cochlear hypoplasia, which when both are present are termed Mondini malformation/dysplasia. Deafness, autosomal recessive 4 (DFNB4) is characterized by nonsyndromic sensorineural hearing impairment, vestibular dysfunction, and enlarged vestibular aqueduct (EVA) without thyroid defects. Both Pendred syndrome and DFNB4 are caused by a partial iodide organification defect. This abnormality can be detected using a perchlorate test, which determines whether iodide is organified normally into thyroglobulin (Bizhanova and Kopp. 2010. PubMed ID: 20298745).

Pendred syndrome and DFNB4 are autosomal recessive disorders that show variable expressivity, even within the same family. They are caused by variants in the solute carrier family 26 member 4 (SLC26A4), (forkhead box I1) FOXI1, and (potassium voltage-gated channel subfamily J member 10) KCNJ10 genes.

Variants in KCNJ10 have been implicated in Pendred syndrome via the role of the KCNJ10 protein in maintaining the endocochlear potential that is necessary for proper auditory function and reduced KCNJ10 expression in the stria vascularis of SLC26A4 knockout mice (Yang et al. 2009. PubMed ID: 19426954). Digenic inheritance of heterozygous variants in SLC26A4 and KCNJ10 has been documented in two families with nonsyndromic hearing loss and EVA (Yang et al. 2009. PubMed ID: 19426954).

Variants in KCNJ10 have also been implicated in a complex syndrome that consists of seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance, or SESAME syndrome (Scholl et al. 2009. PubMed ID: 19289823; Sala-Rabanal et al. 2010. PubMed ID: 20807765). Another disorder related to renal function known as epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST) syndrome is also caused by KCNJ10 variants (Bockenhauer et al. 2009. PubMed ID: 19420365; Reichold et al. 2010. PubMed ID: 20651251). More than 20 causative variants have been reported in the KCNJ10 gene, consisting primarily of missense variants, with a small number of nonsense and small frameshift deletions (Human Gene Mutation Database).

A small population study involving 29 patients with sensorineural hearing loss with inner ear malformations reported that 6.9% of the detected potentially causative variants were in the KCNJ10 gene (Pique et al. 2014. PubMed ID: 24860705). This is considerably higher than a meta-analysis of published studies which showed that 3.1% of suspected DFNB4/Pendred syndrome patients were found to have potentially causative variants in the KCNJ10 gene (Pique et al. 2014. PubMed ID: 24860705).

No large deletions or duplications in KCNJ10 have been reported (Human Gene Mutation Database).

This test provides full coverage of the single coding exon of the KCNJ10 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.