Deafness, X-Linked 2 (DFNX2) via the POU3F4 Gene
Summary and Pricing 
Test Method
Exome Sequencing with CNV Detection
| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 8975 | POU3F4 | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).
Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).
The Sanger Sequencing method for this test is NY State approved.
For Sanger Sequencing click here.Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
X-linked deafness-2 (DFNX2), also referred to as conductive deafness with stapes fixation (DFN3), pertains to a progressive, mixed (includes conductive and sensorineural), prelingual, nonsyndromic hearing loss involving all sound frequencies (Merry et al. 1989; Waryah et al. 2011). This hearing disorder involves abnormalities involving the temporal bone of the inner ear, which is easily detected through computed tomography (CT) examination (Vore et al. 2005; Altay et al. 2008; Santos et al. 2014). The observed anomalies involving the bony labyrinth of the inner ear are usually described as pseudo-Mondini stage II dysplasia (Gharib et al. 2012; Parzefall et al. 2013). Other features of DFNX2 include partial hypoplasia of the cochlea, as well as dilation of the internal auditory canal. DFNX2 also presents with poor transmission of sound between the lateral aspect and the cochlear basal turn (Kumar et al. 2003; Chee et al. 2006). The perilymphatic fluid of the inner ear also creates an outward pressure on the oval window, which inhibits the transmission of vibrations across the stapes bone (Merry et al. 1989; Naranjo et al. 2010). The footplate of the stapes bone and the oval window also show abnormalities that compromise the movement of the ossicle chains of the inner ear (Piussan et al. 1995; Coate et al. 2012). All these structural abnormalities involving inner ear development result in progressive hearing loss.
Genetics
DFNX2 hearing loss disorder follows an X-linked pattern of inheritance and is caused by variants in the POU class 3 homeobox 4 (POU3F4) gene, which has been localized to chromosomal band Xq21.1 (Piussan et al. 1995). Hearing loss and deafness resulting from mutations in the POU3F4 gene affect males, who generally show severe progressive mixed hearing loss and lack or strong reduction of vertibular responses, whereas female carriers show milder audiologic abnormalities and no vestibular dysfunction (Vore et al. 2005).The POU3F4 gene encodes a 361-amino transcription factor that is generally described in terms of its two major components. One component harbors a 75-amino acid DNA-binding domain that is unique to the POU gene family; this domain enhances the binding capacity of DNA. The other component includes a 63-amino acid homeobox domain that commonly occurs among various transcription factors; this region efficiently recognizes specific motifs on the DNA strand for potential binding (Lee et al. 2009). The two DNA-binding domains are linked together by a 17-amino acid polypeptide chain. Most of missense mutations occurring in the POU3F4 gene involve one of these two DNA-binding domains (Vore et al. 2005; Waryah et al. 2011; Parzefall et al. 2013). On the other hand, deletions often involve a regulatory element situated approximately 400 kilobases upstream of the POU3F4 gene (de Kok et al. 1996; Robert-Moreno et al. 2010). Mutations occurring in the POU3F4 gene account for approximately 40% of X-linked deafness cases (Vore et al. 2005). About 60 causative variants have been reported in the POU3F4 gene, which include around 30 missense mutations, 20 small and gross deletions, and a few insertions and other complex rearrangements (Bach et al. 1992; de Kok et al. 1996; Marlin et al. 2009; Waryah et al. 2011; Choi et al. 2013; Parzefall et al. 2013).
Clinical Sensitivity - Sequencing with CNV PGxome
A small cohort study involving 32 familial nonsyndromic hearing loss cases showed that 15.6% of the causative variants were in the POU3F4 gene (Choi et al.2013). Another study involving 17 patients showing clinical features of classical DFN2 showed that 13 patients harbored variants in the POU3F4 gene (de Kok et al. 1996). The analytical sensitivity of this test is expected to be high because most POU3F4 mutations reported to date are expected to be detected by direct sequencing of genomic DNA.
Testing Strategy
This test provides full coverage of all coding exons of the POU3F4 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).
Indications for Test
Any individual who presents with bilateral, progressive, mixed, X-linked hearing loss can be offered the POU3F4 gene test. The individual should have completed otologic and audiologic tests, as well as ancillary testing such as CT imaging of the inner ear to determine the characteristic abnormality involving the temporal bone (Kumar et al. 2003; Altay et al. 2008). Audioprofiling may also assist in determining the rate of progressive hearing loss each year. Cascade testing or successive testing of family members to trace the inheritance pattern of the identified mutation may be offered.
Any individual who presents with bilateral, progressive, mixed, X-linked hearing loss can be offered the POU3F4 gene test. The individual should have completed otologic and audiologic tests, as well as ancillary testing such as CT imaging of the inner ear to determine the characteristic abnormality involving the temporal bone (Kumar et al. 2003; Altay et al. 2008). Audioprofiling may also assist in determining the rate of progressive hearing loss each year. Cascade testing or successive testing of family members to trace the inheritance pattern of the identified mutation may be offered.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| POU3F4 | 300039 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Disease
| Name | Inheritance | OMIM ID |
|---|---|---|
| Deafness, X-Linked 2 | XL | 304400 |
Citations
- Altay H, Savas R, Ogüt F, Kirazli T, Alper H. 2008. CT and MRI findings in X-linked progressive deafness. Diagnostic and Interventional Radiology 14: 117-119. PubMed ID: 18814129
- Bach I, Brunner HG, Beighton P, Ruvalcaba RH, Reardon W, Pembrey ME, van der Velde-Visser SD, Bruns GA, Cremers CW, Cremers FP, Ropers HH. 1992. Microdeletions in patients with gusher-associated, X-linked mixed deafness (DFN3). American Journal of Human Genetics 51: 38-44. PubMed ID: 1609803
- Chee NW, Suhailee S, Goh J. Clinics in diagnostic imaging (111): X-linked congenital mixed deafness syndrome. 2006. Singapore Medical Journal 47: 822-814. PubMed ID: 16924369
- Choi BY, Park G, Gim J, Kim AR, Kim BJ, Kim HS, Park JH, Park T, Oh SH, Han KH, Park WY. 2013. Diagnostic application of targeted resequencing for familial nonsyndromic hearing loss. PLoS One 8: e68692. PubMed ID: 23990876
- Coate TM, Raft S, Zhao X, Ryan AK, Crenshaw EB 3rd, Kelley MW. 2012. Otic mesenchyme cells regulate spiral ganglion axon fasciculation through a Pou3f4/EphA4 signaling pathway. Neuron 73: 49-63. PubMed ID: 22243746
- de Kok YJ, Vossenaar ER, Cremers CW, Dahl N, Laporte J, Hu LJ, Lacombe D, Fischel-Ghodsian N, Friedman RA, Parnes LS, Thorpe P, Bitner-Glindzicz M, Pander HJ, Heilbronner H, Graveline J, den Dunnen JT, Brunner HG, Ropers HH, Cremers FP. 1996. Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4. Human Molecular Genetics 5: 1229-1235. PubMed ID: 8872461
- Gharib B, Esmaeili S, Shariati G, Mazloomi Nobandegani N, Mehdizadeh M. 2012. Recurrent bacterial meningitis in a child with hearing impairment, mondini dysplasia: A case report. Acta Medica Iranica 50: 843-845. PubMed ID: 23456530
- Kumar G, Castillo M, Buchman CA. 2003. X-linked stapes gusher: CT findings in one patient. AJNR American Journal of Neuroradiology 24: 1130-1132. PubMed ID: 12812938
- Lee HK, Song MH, Kang M, Lee JT, Kong KA, Choi SJ, Lee KY, Venselaar H, Vriend G, Lee WS, Park HJ, Kwon TK, Bok J, Kim UK. 2009. Clinical and molecular characterizations of novel POU3F4 mutations reveal that DFN3 is due to null function of POU3F4 protein. Physiological Genomics 39: 195-201. PubMed ID: 19671658
- Marlin S, Moizard MP, David A, Chaissang N, Raynaud M, Jonard L, Feldmann D, Loundon N, Denoyelle F, Toutain A. 2009. Phenotype and genotype in females with POU3F4 mutations. Clinical Genetics 76: 558-563. PubMed ID: 19930154
- Merry DE, Lesko JG, Sosnoski DM, Lewis RA, Lubinsky M, Trask B, van den Engh G, Collins FS, Nussbaum RL. 1989. Choroideremia and deafness with stapes fixation: a contiguous gene deletion syndrome in Xq21. American Journal of Human Genetics 45: 530-540. PubMed ID: 2491012
- Naranjo S1, Voesenek K, de la Calle-Mustienes E, Robert-Moreno A, Kokotas H, Grigoriadou M, Economides J, Van Camp G, Hilgert N, Moreno F, Alsina B, Petersen MB, Kremer H, Gómez-Skarmeta JL. 2010. Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing. Human Genetics 128: 411-419. PubMed ID: 20668882
- Parzefall T, Shivatzki S, Lenz DR, Rathkolb B, Ushakov K, Karfunkel D, Shapira Y, Wolf M, Mohr M, Wolf E, Sabrautzki S, de Angelis MH, Frydman M, Brownstein Z, Avraham KB. 2013. Cytoplasmic mislocalization of POU3F4 due to novel mutations leads to deafness in humans and mice. Human Mutation 34: 1102-1110. PubMed ID: 23606368
- Piussan C, Hanauer A, Dahl N, Mathieu M, Kolski C, Biancalana V, Heyberger S, Strunski V. 1995. X-linked progressive mixed deafness: A new microdeletion that involves a more proximal region in Xq21. American Journal of Human Genetics 56: 224-230. PubMed ID: 7825582
- Robert-Moreno À, Naranjo S, de la Calle-Mustienes E, Gómez-Skarmeta JL, Alsina B. 2010. Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns. PLoS One 5: e15907. PubMed ID: 21209840
- Santos S, Domínguez MJ, Cervera J, Suárez A, Bueno A, Bartolomé M, López R. 2014. Hearing loss and enlarged internal auditory canal in children. Acta Otorrinolaringologica Espanola 65: 93-101. PubMed ID: 24534420
- Vore AP, Chang EH, Hoppe JE, Butler MG, Forrester S, Schneider MC, Smith LL, Burke DW, Campbell CA, Smith RJ. 2005. Deletion of and novel missense mutation in POU3F4 in 2 families segregating X-linked nonsyndromic deafness. Archives of Otolaryngology Head and Neck Surgery 131: 1057-1063. PubMed ID: 16365218
- Waryah AM, Ahmed ZM, Bhinder MA, Choo DI, Sisk RA, Shahzad M, Khan SN, Friedman TB, Riazuddin S, Riazuddin S. 2011. Molecular and clinical studies of X-linked deafness among Pakistani families. Journal of Human Genetics 56: 534-540. PubMed ID: 21633365
Ordering/Specimens
Ordering Options
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Requisition Form
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For Requisition Forms, visit our Forms page
If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.
Specimen Types
Specimen Requirements and Shipping Details
PGxome (Exome) Sequencing Panel
PGnome (Genome) Sequencing Panel
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