Deafness, Autosomal Dominant 69 (DFNA69), and Familial Progressive Hyperpigmentation with or without Hypopigmentation via the KITLG 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
4433 KITLG$750.00 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 sequencing test is not precisely known. Only six point and two small insertion/deletion variants in the KITLG gene have been reported as pathogenic (Human Gene Mutation Database). Analytical sensitivity should be high because all reported variants are detectable by sequencing.

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Clinical Features

Nonsyndromic hearing loss is characterized by difficulty or inability to hear that is not associated with any visible defects involving the external ear, other organs, or any other medical condition. Nonsyndromic hearing loss may be associated with abnormalities involving the middle ear and/or the inner ear (Ciuman 2013; Dodson et al. 2011; Hilgert et al. 2009). At least 70% of cases involving hearing loss are nonsyndromic (Van Camp et al. 1997).

Nonsyndromic hearing loss and deafness due to pathogenic variants in the KITLG gene is associated with congenital or prelingual, mild to profound, asymetric, unilateral or bilateral, non-progressive sensorineural hearing impairment with overall variable penetrance. No vestibular abnormalities are present. Furthermore, no pigmentation effects were detected in two families with hearing loss due to variants in the KITLG gene (Zazo Seco et al. 2015).

Pathogenic variants in the KITLG gene also cause familial progressive hyperpigmentation with or without hypopigmentation, associated with diffuse hyperpigmentation, cafe-au-lait macules and larger hypopigmented ash-leaf macules on the face, neck, trunk and limbs. Onset is congenital or early infancy and progressive with large areas of the skin becoming hyperpigmented. Hearing was not reported as being affected in patients with pigmentation effects (Wang et al. 2009; Amyere et al. 2011).

The KITLG gene has also been suggested as the cause of hearing loss, heterochromia iridum with skin hyper- and hypopigmentation in a single Dutch family. These features along with the absence of dystopia canthorum in this family had resulted in a diagnosis of Waardenburg syndrome type II prior to genetic testing, indicating that variants in the KITLG gene may also cause this auditory-pigmentary disorder (Zazo Seco et al. 2015).


The KIT ligand (KITLG) gene is located on chromosome 12q21.32 and spans 91.7 kb, consisting of 9 coding exons that produce a 273 amino acid protein. The KITLG protein (also known as steel factor, stem cell factor, and mast cell growth factor) is the ligand for the KIT tyrosine-kinase receptor. KITLG is involved in proliferation and migration of neural crest cells as well as survival and differentiation of hematopoietic precursor cells, primordial germ cells and melanoblasts (Zazo Seco et al. 2015). KIT signaling causes post-translational modification of the MITF protein, a key transcription factor involved in the survival, proliferation and differentiation of melanoblasts as well as regulating the expression of genes involved in pigment production (Zazo Seco et al. 2015; Lin and Fisher 2007).

The mechanism by which KITLG variants cause sensorineural hearing loss is not completely understood, although it is thought to be mediated by melanocytes in the stria vascularis of the inner ear that are necessary for generating the endocochlear potential involved in the detection of sound (Kim et al. 2015; Cable et al. 1992).

Six missense, one small deletion and one premature protein termination variant in the KITLG gene have been reported as pathogenic, all of which were inherited in an autosomal dominant manner (Wang et al. 2009; Amyere et al. 2011; Cuell et al. 2015; Zazo Seco et al. 2015).

Testing Strategy

This test involves bidirectional Sanger DNA sequencing of all coding exons of the KITLG 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) in family members of patients with a known mutation or to confirm research results.

Indications for Test

Patients with nonsyndromic hearing loss; skin hyper/hypopigmentation; or both of these in combination with hair and eye pigmentation abnormalities suggestive of Waardenburg syndrome type II.


Official Gene Symbol OMIM ID
KITLG 184745
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Genetic Counselors
  • Amyere M. et al. 2011. The Journal of Investigative Dermatology. 131: 1234-9. PubMed ID: 21368769
  • Cable J. et al. 1992. Hearing Research. 64:6-20. PubMed ID: 1490901
  • Ciuman R.R. 2013. Medical Science Monitor. 19: 1195-210. PubMed ID: 24362017
  • Cuell A. et al. 2015. Clinical and Experimental Dermatology. 40:860-4. PubMed ID: 26179221
  • Dodson K.M. et al. 2011. American Journal of Medical Genetics. Part A. 155A: 993-1000. PubMed ID: 21465647
  • Hilgert N. et al. 2009. Mutation Research. 681: 189-96. PubMed ID: 18804553
  • Human Gene Mutation Database (Bio-base).
  • Kim S.H. et al. 2015. Medicine. 94:e1817. PubMed ID: 26512583
  • Lin J.Y. and Fisher D.E. 2007. Nature. 445: 843-50. PubMed ID: 17314970
  • Van Camp G. et al. 1997. American Journal of Human Genetics. 60: 758-64. PubMed ID: 9106521
  • Wang Z.Q. et al. 2009. American Journal of Human Genetics. 84:672-7. PubMed ID: 19375057
  • Zazo Seco C. et al. 2015. American Journal of Human Genetics. 97:647-60. PubMed ID: 26522471
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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.

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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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