Pendred Syndrome and Nonsyndromic Hearing Loss Associated with Enlarged Vestibular Aqueduct via the SLC26A4 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). Thyroid defects are not seen in DFNB4. 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 overall 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 the FOXI1 and KCNJ10 genes have also been reported in patients with nonsyndromic hearing loss and EVA and a single SLC26A4 variant (Yang et al. 2007. PubMed ID: 17503324; Yang et al. 2009. PubMed ID: 19426954).

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 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 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SLC26A4 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

In addition to the regions described above, this test includes coverage of the following variants that reside in untranslated or deep intronic regions: SLC26A4 non-coding exon 1 (including c.-103T>C, c.-60A>G and c.-4+1G>C).