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Original Investigation |

Use of SLC26A4 Mutation Testing for Unilateral Enlargement of the Vestibular Aqueduct

Parna Chattaraj, MS1; Fabian R. Reimold, MD, PhD2; Julie A. Muskett, MS1; Boris E. Shmukler, PhD2; Wade W. Chien, MD3; Anne C. Madeo, MS1; Shannon P. Pryor, MD1; Christopher K. Zalewski, MA1; John A. Butman, MD, PhD4; Carmen C. Brewer, PhD1; Margaret A. Kenna, MD, MPH5,6; Seth L. Alper, MD, PhD2; Andrew J. Griffith, MD, PhD1
[+] Author Affiliations
1Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland
2Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
3Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland
4Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland
5Departments of Otolaryngology and Communication Enhancement, Boston Childrens’ Hospital, Boston, Massachusetts
6Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts
JAMA Otolaryngol Head Neck Surg. 2013;139(9):907-913. doi:10.1001/jamaoto.2013.4185.
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Importance  Approximately one-half of all subjects with unilateral or bilateral hearing loss with enlargement of the vestibular aqueduct (EVA) will have SLC26A4 gene mutations. The number (0, 1, or 2) of mutant alleles of SLC26A4 detected in an individual subject with EVA is each associated with a distinct combination of diagnostic and prognostic information as well as probability of recurrence of EVA in siblings.

Objective  To evaluate the results of SLC26A4 mutation testing in subjects with unilateral EVA. (The study objective was formulated before data were collected.)

Design  Prospective cross-sectional study of cohort ascertained between 1998 and 2012.

Setting  National Institutes of Health Clinical Center, a federal biomedical research facility.

Participants  Twenty-four subjects (10 males, 14 females) with unilateral EVA, defined as a midpoint diameter greater than 1.5 mm, who were referred or self-referred to participate in a study about the clinical and molecular analysis of EVA. Twenty-one (87.5%) of 24 subjects were white. Mean age was 10.3 years (age range, 5-39 years).

Intervention  SLC26A4 mutation analysis.

Main Outcomes and Measures  Audiometric results, the presence or absence of EVA, and the number of mutant alleles of SLC26A4.

Results  Approximately 8.3% of the subjects with unilateral EVA had 2 mutant SLC26A4 alleles, 16.7% had 1 mutant allele, and 75.0% had 0 mutant alleles.

Conclusions and Relevance  Unilateral EVA can be associated with all possible SLC26A4 genotype results. The distinct combination of prognoses and recurrence probability associated with each genotype supports the clinical use of testing for SLC26A4 mutations in subjects with unilateral EVA.

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Figure 1.
Pure-Tone Audiograms

A, Subject 1627 at age 5 years. B and C, Subject 2026 at age 6 (B) and 10 (C) years. Air-bone conduction threshold gaps are consistent with cochlear conductive hearing loss observed in some ears with enlargement of vestibular aqueduct.14 RE indicates right ear; LE, left ear; dB, decibels; HL, hearing loss; and ANSI, American National Standards Institute.

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Figure 2.
Temporal Bone Images

A-D, Axial magnetic resonance and computed tomographic (E and F) images of right (A, C, and E) and left (B, D, and F) temporal bones of subjects 1627 (A and B) and 2026 (C-F). Scale bars (A and C) indicate 1 cm; arrows indicate an enlarged endolymphatic duct and sac (A and D) or enlargement of the vestibular aqueduct (F).

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Figure 3.
Anion Transport Function

A, Chlorine-36 (36Cl-) influx into uninjected Xenopus oocytes or oocytes expressing wild-type (WT) or mutant pendrin (R185T). B, 36Cl- efflux from WT or R185T mutant pendrin-expressing oocytes exposed sequentially to salt bath compositions are shown. C and D, 36Cl- efflux rate constants. E, Pendrin-GFP variants and normalized fluorescence intensity (FI) at surface of oocytes. F, WT or R185T mutant pendrin (green) and concanavalin-A staining (red) of plasma membranes8 of COS-7 cells. Co-localization of WT pendrin with concanavalin-A at the plasma membrane is seen as yellow (green arrow), while R185T mutant pendrin does not localize to the plasma membrane (red arrow). Scale bars indicate 20 μm; mM, millimolar; In, natural logarithm; I, iodine ion; and HCO3, bicarbonate ion.

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