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Deafness, X-linked 6 (DFNX6) via the COL4A6 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
11195 COL4A6 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11195COL4A681479 81479(x2) $890 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 backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Ben Dorshorst, PhD

Clinical Features and Genetics

Clinical Features

X-linked deafness 6 (DFNX6) is a postlingual, progressive sensorineural type of hearing loss of variable severity that is responsible for around 1% of nonsyndromic hearing loss cases (ACMG 2002). Sensorineural deafness generally results from damage to the neural receptors of  the inner ear, the nerve pathways leading to the brain, or the region of the brain that receives sound information. To date, only one study has described DFNX6 in a three-generation Hungarian family with 4 males diagnosed with severe bilateral sensorineural hearing loss during infancy (Rost et al. 2014). Magnetic resonance imaging of the brain of the 3-year-old proband showed bilateral malformation of the cochlea, mainly presenting incomplete separation from the internal auditory canal. The proband was then subjected to cochlear implantation, which resulted in profuse release of cerebrospinal fluid after surgically opening the cochlea, which is also known as the 'gusher' phenomenon. The other 3 affected males presented with the same cochlear structural abnormality. Hearing loss in all four affected males was determined to be of prelingual onset. Four of the female family members developed mild to moderate hearing impairment during the third and fourth decades of life, whereas another female member developed mild hearing loss at age 9. The 46-year-old mother of the proband showed no hearing impairment nor cochlear malformation on brain imaging.

Genetics

DFNX6 is an X-linked nonsyndromic, postlingual, sensorineural type of hearing loss caused by pathogenic sequence variants in the collagen type IV alpha-6 (COL4A6) gene. COL4A6 encodes a 1,678-amino acid collagen isoform that assembles in a head-to-head conformation with two collagen type IV alpha-5 chains, forming a triple-helical molecule that serves as a component of the cellular basement membrane (Zhou et al. 1994). The basement membrane plays a key role in the compartmentalization of tissues as well as in the transmission of molecular signals for cellular differentiation (Miner 1999; Thielen et al. 2003). Other members of the type IV collagen gene family include COL4A1, COL4A2, COL4A3, and COL4A4, with COL4A2 and COL4A4 showing the highest DNA sequence homology to COL4A6 (Oohashi et al. 1995). The COL4A6 gene is approximately 425 kb in length, consists of 45 exons, and has been localized to chromosomal region Xq22 (Oohashi et al. 1994).

To date, only one study has been conducted on DFNX6 via the COL4A6 gene. In a three-generation Hungarian family of 17 available members, all four affected males were determined to be hemizygous for the same causative missense variant in the COL4A6 gene (Rost et al. 2014). The four affected males were also pre-determined to have no pathogenic sequence variants in the other more common X-linked deafness genes such as PRPS1 and POU3F4. All four obligatory female carriers and one slightly affected female member were heterozygous for the same pathogenic sequence variant. All unaffected male family members did not harbor the causative missense substitution.

Clinical Sensitivity - Sequencing with CNV PGxome

Because only one report has described a single COL4A6 pathogenic variant, it is difficult to estimate the clinical sensitivity of this test.

Testing Strategy

This test provides full coverage of all coding exons of the COL4A6 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

Candidates for this test are patients with hearing loss that apparently follows an X-linked pattern of inheritance.

Gene

Official Gene Symbol OMIM ID
COL4A6 303631
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Deafness, X-linked 6 XL 300914

Citations

  • ACMG. Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss. Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics in Medicine 2002 4(3): 162-171. PubMed ID: 12180152
  • Hertz JM. 2009. Alport syndrome. Molecular genetic aspects. Dan Med Bull 56: 105–152. PubMed ID: 19728970
  • Miner JH. 1999. Alport syndrome with diffuse leiomyomatosis. When and when not? American Journal of Pathology 154(6): 1633-1635. PubMed ID: 10362786
  • Oohashi T, Sugimoto M, Mattei MG, Ninomiya Y. 1994. Identification of a new collagen IV chain, alpha 6(IV), by cDNA isolation and assignment of the gene to chromosome Xq22, which is the same locus for COL4A5. Journal of Biological Chemistry 269(10): 7520-7526. PubMed ID: 8125972
  • Oohashi T, Ueki Y, Sugimoto M, Ninomiya Y. 1995. Isolation and structure of the COL4A6 gene encoding the human alpha 6(IV) collagen chain and comparison with other type IV collagen genes. Journal of Biological Chemistry 270(45): 26863-26867. PubMed ID: 7592929
  • Rost S, Bach E, Neuner C, Nanda I, Dysek S, Bittner RE, Keller A, Bartsch O, Mlynski R, Haaf T, Müller CR, Kunstmann E. 2014. Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6. Eur. J. Hum. Genet. 22: 208-215. PubMed ID: 23714752
  • Thielen BK, Barker DF, Nelson RD, Zhou J, Kren SM, Segal Y. 2003. Deletion mapping in Alport syndrome and Alport syndrome-diffuse leiomyomatosis reveals potential mechanisms of visceral smooth muscle overgrowth. Human Mutation 22(5): 419. PubMed ID: 14517961
  • Zhou J1, Ding M, Zhao Z, Reeders ST. 1994. Complete primary structure of the sixth chain of human basement membrane collagen, alpha 6(IV). Isolation of the cDNAs for alpha 6(IV) and comparison with five other type IV collagen chains. Journal of Biological Chemistry 269(18): 13193-13199. PubMed ID: 8175748

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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