Pendred Syndrome and Nonsyndromic Hearing Loss Associated with Enlarged Vestibular Aqueduct Panel

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 SLC26A4 are the third most common cause of autosomal recessive hearing loss and explain 50% of Pendred syndrome and DFNB4 cases (Smith. 2017. PubMed ID: 20301640; Hilgert et al. 2009. PubMed ID: 18804553). SLC26A4, which encodes the pendrin protein, is a chloride, iodide, bicarbonate, and formate transporter. Pendrin is expressed in the thyroid, the inner ear, and the kidney (Bizhanova and Kopp. 2010. PubMed ID: 20298745). Individuals with Pendred syndrome or DFNB4 are often compound heterozygous for variants in SLC26A4, but only one heterozygous causative variant is found in approximately 10% and 25% of Asian and White families, respectively (Smith. 2017. PubMed ID: 20301640). More than 400 causative variants have been reported in SLC26A4 consisting of missense, nonsense, splicing, regulatory, small frameshift insertions/deletions and large deletions (Human Gene Mutation Database).

Variants in FOXI1 have been implicated in Pendred syndrome via the role of the FOXI1 protein in transcriptional activation of SLC26A4 (Yang et al. 2007. PubMed ID: 17503324). Digenic inheritance of heterozygous variants in SLC26A4 and FOXI1 has been documented in one family with nonsyndromic hearing loss and EVA (Yang et al. 2007. PubMed ID: 17503324). Less than 10 causative variants have been reported in FOXI1, consisting of missense variants and small in-frame deletions (Human Gene Mutation Database).

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).

Variants in SLC26A4 are the third most common cause of autosomal recessive hearing loss overall and explain 50% of Pendred syndrome and DFNB4 cases (Smith. 2017. PubMed ID: 20301640; Hilgert et al. 2009. PubMed ID: 18804553). A small population study involving 29 patients with sensorineural hearing loss with inner ear malformations reported that 3.4% of the detected potentially causative variants were in the FOXI1 gene and 6.9% 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 1.3% and 3.1% of suspected DFNB4/Pendred syndrome patients were found to have potentially causative variants in the FOXI1 and KCNJ10 genes, respectively (Pique et al. 2014. PubMed ID: 24860705).

A study involving 107 patients with sensorineural hearing loss with inner ear malformations and a single heterozygous causative variant in SLC26A4 identified a large deletion in only a single patient, indicating the clinical sensitivity for deletion and duplication analysis is low (Pique et al. 2014. PubMed ID: 24860705). Only 6 large deletions have been reported in SLC26A4 and no large deletions or duplications in FOXI1 and KCNJ10 have been reported (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).