Pendred Syndrome and Nonsyndromic Hearing Loss Associated with Enlarged Vestibular Aqueduct Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10051 FOXI1 81479,81479 Order Options and Pricing
KCNJ10 81404,81479
SLC26A4 81406,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10051Genes x (3)81479 81404, 81406, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

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Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Pendred syndrome is a congenital or prelingual sensorineural hearing impairment disorder that generally causes severe to profound hearing loss and other findings. Clinical features, in addition to hearing loss, can include an enlarged vestibular aqueduct (EVA), temporal bone abnormalities, and development of euthyroid goiter in late childhood to early adulthood (Smith. 2017. PubMed ID: 20301640). Individuals with Pendred syndrome who have EVA can also have cochlear hypoplasia, which when both are present are termed Mondini malformation/dysplasia. Deafness, autosomal recessive 4 (DFNB4) is characterized by nonsyndromic sensorineural hearing impairment, vestibular dysfunction, and enlarged vestibular aqueduct (EVA) without thyroid defects. Both Pendred syndrome and DFNB4 are caused by a partial iodide organification defect. This abnormality can be detected using a perchlorate test, which determines whether iodide is organified normally into thyroglobulin (Bizhanova and Kopp. 2010. PubMed ID: 20298745).

Genetics

Pendred syndrome and DFNB4 are autosomal recessive disorders that show variable expressivity, even within the same family. They are caused by variants in the solute carrier family 26 member 4 (SLC26A4), (forkhead box I1) FOXI1, and (potassium voltage-gated channel subfamily J member 10) KCNJ10 genes.

Variants in SLC26A4 are the third most common cause of autosomal recessive hearing loss and explain 50% of Pendred syndrome and DFNB4 cases (Smith. 2017. PubMed ID: 20301640; Hilgert et al. 2009. PubMed ID: 18804553). SLC26A4, which encodes the pendrin protein, is a chloride, iodide, bicarbonate, and formate transporter. Pendrin is expressed in the thyroid, the inner ear, and the kidney (Bizhanova and Kopp. 2010. PubMed ID: 20298745). Individuals with Pendred syndrome or DFNB4 are often compound heterozygous for variants in SLC26A4, but only one heterozygous causative variant is found in approximately 10% and 25% of Asian and Caucasian families, respectively (Smith. 2017. PubMed ID: 20301640). More than 400 causative variants have been reported in SLC26A4 consisting of missense, nonsense, splicing, regulatory, small frameshift insertions/deletions and large deletions (Human Gene Mutation Database).

Variants in FOXI1 have been implicated in Pendred syndrome via the role of the FOXI1 protein in transcriptional activation of SLC26A4 (Yang et al. 2007. PubMed ID: 17503324). Digenic inheritance of heterozygous variants in SLC26A4 and FOXI1 has been documented in one family with nonsyndromic hearing loss and EVA (Yang et al. 2007. PubMed ID: 17503324). Less than 10 causative variants have been reported in FOXI1, consisting of missense variants and small in-frame deletions (Human Gene Mutation Database).

Variants in KCNJ10 have been implicated in Pendred syndrome via the role of the KCNJ10 protein in maintaining the endocochlear potential that is necessary for proper auditory function and reduced KCNJ10 expression in the stria vascularis of SLC26A4 knockout mice (Yang et al. 2009. PubMed ID: 19426954). Digenic inheritance of heterozygous variants in SLC26A4 and KCNJ10 has been documented in two families with nonsyndromic hearing loss and EVA (Yang et al. 2009. PubMed ID: 19426954).

Variants in KCNJ10 have also been implicated in a complex syndrome that consists of seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance, or SESAME syndrome (Scholl et al. 2009. PubMed ID: 19289823; Sala-Rabanal et al. 2010. PubMed ID: 20807765). Another disorder related to renal function known as epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST) syndrome is also caused by KCNJ10 variants (Bockenhauer et al. 2009. PubMed ID: 19420365; Reichold et al. 2010. PubMed ID: 20651251). More than 20 causative variants have been reported in the KCNJ10 gene, consisting primarily of missense variants, with a small number of nonsense and small frameshift deletions (Human Gene Mutation Database).

Clinical Sensitivity - Sequencing with CNV PGxome

Variants in SLC26A4 are the third most common cause of autosomal recessive hearing loss overall and explain 50% of Pendred syndrome and DFNB4 cases (Smith. 2017. PubMed ID: 20301640; Hilgert et al. 2009. PubMed ID: 18804553). A small population study involving 29 patients with sensorineural hearing loss with inner ear malformations reported that 3.4% of the detected potentially causative variants were in the FOXI1 gene and 6.9% in the KCNJ10 gene (Pique et al. 2014. PubMed ID: 24860705). This is considerably higher than a meta-analysis of published studies which showed that 1.3% and 3.1% of suspected DFNB4/Pendred syndrome patients were found to have potentially causative variants in the FOXI1 and KCNJ10 genes, respectively (Pique et al. 2014. PubMed ID: 24860705).

A study involving 107 patients with sensorineural hearing loss with inner ear malformations and a single heterozygous causative variant in SLC26A4 identified a large deletion in only a single patient, indicating the clinical sensitivity for deletion and duplication analysis is low (Pique et al. 2014. PubMed ID: 24860705). Only 6 large deletions have been reported in SLC26A4 and no large deletions or duplications in FOXI1 and KCNJ10 have been reported (Human Gene Mutation Database).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Individuals with sensorineural hearing loss and enlarged vestibular aqueduct (EVA). Individuals may also display temporal bone abnormalities, euthyroid goiter, cochlear hypoplasia, Mondini malformation/dysplasia or positive perchlorate discharge test.

Genes

Official Gene Symbol OMIM ID
FOXI1 601093
KCNJ10 602208
SLC26A4 605646
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Bizhanova and Kopp. 2010. PubMed ID: 20298745
  • Bockenhauer et al. 2009. PubMed ID: 19420365
  • Hilgert et al. 2009. PubMed ID: 18804553
  • Human Gene Mutation Database (Bio-base).
  • Pique et al. 2014. PubMed ID: 24860705
  • Reichold et al. 2010. PubMed ID: 20651251
  • Sala-Rabanal et al. 2010. PubMed ID: 20807765
  • Scholl et al. 2009. PubMed ID: 19289823
  • Smith. 2017. PubMed ID: 20301640
  • Yang et al. 2007. PubMed ID: 17503324
  • Yang et al. 2009. PubMed ID: 19426954

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.

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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

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