Deafness, Autosomal Recessive 49 (DFNB49) via the MARVELD2 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1851 MARVELD2$810.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

The clinical sensitivity of this test has been reported to range from 0.1% to 11.8%. Causative variants in the MARVELD2 gene were detected in 0.6% (1/160) of families with autosomal recessive nonsyndromic hearing loss (Bademci et al. 2015). In Iran, 0.7% (1/144) of families with autosomal recessive nonsyndromic hearing loss harbored pathogenic MARVELD2 sequence variants (Babanejad et al. 2012). Around 1% (3/284) of Pakistani families diagnosed with autosomal recessive nonsyndromic hearing loss harbored causative sequence variants in the MARVELD2 gene (Chisti et al. 2008). In two independent research studies conducted in Japan, around 0.1% (1/1,20; Nishio and Usami 2015) and 1.9% (4/216; Miyagawa et al. 2013) of deaf patients tested positive for pathogenic MARVELD2 sequence variants. In Turkey, pathogenic sequence variants in the MARVELD2 gene were detected in 3.4% (1/29) of families with autosomal recessive nonsyndromic hearing loss (Atik et al. 2015). Diseasing-causing MARVELD2 sequence variants were observed in 4.2% (6/143) of deaf Slovakian families who tested negative for GJB2 pathogenic sequence variants and 11.8% (10/85) of Hungarian patients with hearing impairment (Masindova et al. 2015).  

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 MARVELD2$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features

Autosomal recessive deafness 49 (DFNB49) is characterized by prelingual, bilateral, moderate to profound, stable, all-frequency, symmetrical, sensorineural nonsyndromic hearing loss (Chisti et al. 2008). The audioprofile of most nonsyndromic hearing loss cases can be distinct, thus assisting in the development of an evaluation strategy for molecular genetic testing and in generating a prognosis on the rate of hearing loss per year (Hildebrand et al. 2008). Pure-tone audiometry of DFNB49 individuals is usually flat, indicating hearing loss at all frequencies (Ramzan et al. 2008; Chisti et al. 2008). Individuals diagnosed with DFNB49 generally do not present with features of visual loss, deformities involving the limbs, mental deficiency, or disruption of vestabular organization.


DFNB49 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the marvel domain-containing protein 2 (MARVELD2) gene, which is located on chromosome 5q13.2 (Ramzan et al. 2005). The MARVELD2 gene consists of 6 coding exons that encode a 558-amino acid membrane protein known as tricellulin, which plays a major role in the regulation of movement of solutes across cells and tissues (Ikenouchi et al. 2005; Riazuddin et al. 2006; Higashi et. al. 2013). In the epithelial cells of the inner ear, tricellulin is expressed in the tricellular tight junctions, which are regions within the organ of Corti that contain potassium ion (K+)-rich endolymphatic fluid that is required for the conduction of sound (Kitajiri et al. 2004). The presence of tricellulin in the inner ear epithelial cells ensures tightness in these cellular junctions, which is essential for hearing (Chisti et al. 2008). Previous studies have suggested that deafness is caused by an increase in either the concentration of K+ ions or small molecules such as adenosine triphosphate (ATP) around the hair bundle, which results in an abnormal endocochlear potential, ultimately resulting in hair cell dysfunction and degeneration (Mariano et al. 2011; Higashi et al. 2013). Gene knockout studies using a mouse model showed early-onset hearing loss that was associated with the degeneration of inner ear hair cells (Nayak et al. 2013; Kamitani et al. 2015). To date, a total of about 13 pathogenic MARVELD2 sequence variants have been reported, which include 5 missense/nonsense, 4 splicing, 3 small deletions, and 1 gross deletion (Human Gene Mutation Database).

Testing Strategy

This test involves bidirectional Sanger DNA sequencing of all coding exons of the MARVELD2 gene. The entire coding region and ~10 bp of flanking non-coding DNA on either side of each splice site are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

The ideal MARVELD2 test candidates are individuals who present with prelingual, bilateral, moderate to profound, stable, all-frequency, symmetrical, autosomal recessive nonsyndromic hearing loss.


Official Gene Symbol OMIM ID
MARVELD2 610572
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Deafness, Autosomal Recessive 49 610153

Related Test

Nonsyndromic Hearing Loss and Deafness Sequencing Panel


Genetic Counselors
  • Atik T. et al. 2015. Plos One. 10: e0142154. PubMed ID: 26561413
  • Babanejad M. et al. 2012. American Journal of Medical Genetics. Part A. 158A: 2485-92. PubMed ID: 22903915
  • Bademci G. et al. 2015. Genetics in Medicine : Official Journal of the American College of Medical Genetics. 0: N/A. PubMed ID: 26226137
  • Chishti M.S. et al. 2008. Journal of Human Genetics. 53: 101-5. PubMed ID: 18084694
  • Higashi T. et al. 2013. The Journal of Clinical Investigation. 123: 3712-5. PubMed ID: 23979155
  • Hildebrand M.S. et al. 2008. Genetics in Medicine. 10: 797-804. PubMed ID: 18941426
  • Human Gene Mutation Database (Bio-base).
  • Ikenouchi J. et al. 2005. The Journal of Cell Biology. 171: 939-45. PubMed ID: 16365161
  • Kamitani T. et al. 2015. Scientific Reports. 5: 18402. PubMed ID: 26677943
  • Kitajiri S. et al. 2004. Journal of Cell Science. 117: 5087-96. PubMed ID: 15456848
  • Mariano C. et al. 2011. European Journal of Cell Biology. 90: 787-96. PubMed ID: 21868126
  • Mašindová I. et al. 2015. Plos One. 10: e0124232. PubMed ID: 25885414
  • Miyagawa M. et al. 2013. PLoS One. 8: e71381. PubMed ID: 23967202
  • Nayak G. et al. 2013. The Journal of Clinical Investigation. 123: 4036-49. PubMed ID: 23979167
  • Nishio SY., Usami S. 2015. The Annals of Otology, Rhinology, and Laryngology. 124 Suppl 1: 49S-60S. PubMed ID: 25788563
  • Ramzan K. et al. 2005. Human Genetics. 116: 17-22. PubMed ID: 15538632
  • Riazuddin S. et al. 2006. American Journal of Human Genetics. 79: 1040-51. PubMed ID: 17186462
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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