Pendred Syndrome and Nonsyndromic Hearing Loss Associated with Enlarged Vestibular Aqueduct via the FOXI1 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 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).

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 (Pique et al. 2014. PubMed ID: 24860705). This is considerably higher than a meta-analysis of published studies which showed that 1.3% of suspected DFNB4/Pendred syndrome patients were found to have potentially causative variants in the FOXI1 gene (Pique et al. 2014. PubMed ID: 24860705).

This test provides full coverage of all coding exons of the FOXI1 gene 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 full 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).