POU3F4
The Clinical Diagnostics Service of the Molecular Otolaryngology Research Laboratory is a Joint Commission-approved CLIA-accredited diagnostic laboratory that offers mutation screening of several genes.

DFN3 (OMIM#: # 304400)
Deafness at the DFN3 locus can be conductive (due to impaired stapes mobility) and/or mixed with a superimposed, often progressive, sensorineural component. Stapedectomy to correct the conductive component is contraindicated because of the possibility of iatrogenic profound hearing loss secondary to a stapes gusher. A stapes gusher occurs because the internal auditory canal is abnormally dilated. The wide communication between the internal auditory canal and inner ear can often be visualized by computerized tomography. The gene, POU3F4, was found to be responsible for this form of X-linked hearing loss by De Kok and colleagues.

POU3F4 (OMIM#: #300039)
The single exon of POU3F4 encodes a transcription factor with a 75 amino acid POU domain and a 63 amino acid homeobox domain. In animal studies, Minowa and colleagues showed Brn4 (Pou3f4) deficient mice have profound deafness and inner ear abnormalities. In humans with DFN3, mutations have been found in either of the two binding domains, as well as upstream of POU3F4. In the presence of these large upsteam deletions, the coding sequence of POU3F4 can be entirely normal.

MORL screening methodology
Screening for POU3F4 is performed by sequencing and STRP analysis. The initial screening test uses oligonucleotide primers that amplify the exon of POU3F4 followed by direct sequencing to determine whether mutations lie within the POU3F4 gene. In the absence of a POU3F4 coding mutation, the upstream region of POU3F4 is screened for a possible deletion by running 8 STSs that cover approximately 1200 kB of genomic DNA at regularly spaced intervals. These markers are PCR amplified, resolved by gel electrophoresis and scored as present or absent.

Sensitivity
Sensitivity is greater than 99% for coding sequence analysis of POU3F4. The sensitivity of the deletion screen is unknown (see Vore et al., 2005 for a review).

Turn-around time
Turn around time is approximately 3 months.

Cost: $400

Indications for screening
This test is appropriate for persons with X-linked nonsydromic hearing loss. Computed tomography of the temporal bones may show pseudo-Mondini stage II dysplasia, which includes hypoplasia of the cochlea and dilation of the internal auditory canal.

GeneTests  GeneReviews – Deafness and Hereditary Hearing Loss: Overview

References
Phelps, P. D. et al.: X-linked deafness, stapes gushers and a distinctive defect of the inner ear. Neuroradiology 33: 326-330, 1991.
PubMed ID:  1922747
PubMed Search

De Kok, Y. J. M. et al.: Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science 267: 685-688, 1995.
PubMed ID: 7839145
PubMed Search

Minowa, O.: Altered cochlear fibrocytes in a mouse model of DFN3 nonsyndromic deafness.Science 285: 1408-1411, 1999.
PubMed ID: 10464101
PubMed Search

Vore, A. P., et al.: Deletion of and novel missense mutation in POU3F4 in 2 families segregating X-linked nonsyndromic deafness.
Arch Otolaryngol Head Neck Surg. 2005 Dec;131(12):1057-63
PubMed ID: 16365218
PubMed Search