Targeted Next-Generation Sequencing Facilitates Genetic Diagnosis and Provides Novel Pathogenetic Insights into Deafness with Enlarged Vestibular Aqueduct

Enlarged vestibular aqueduct (EVA) is an inner-ear malformation associated with sensorineural hearing impairment. Most EVAs are associated with Pendred syndrome and nonsyndromic autosomal recessive deafness–4 (DFNB4), two autosomal-recessive disorders caused by mutations in SLC26A4. However, many EVA patients cannot have a confirmed diagnosis by screening common SLC26A4 mutations, constituting an enigma in genetic diagnosis. To enable comprehensive genetic examination and explore the etiologies of EVA, we designed a next-generation sequencing panel targeting the entire length of 3 Pendred syndrome/DFNB4 genes (SLC26A4, FOXI1, and KCNJ10) and exons of 10 other genes related to EVA and performed genetic testing in 50 EVA families without confirmative results on screening for SLC26A4 hotspots (c.919-2A>G and p.H723R).