Waardenburg Syndrome Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesGene CPT Codes Copy CPT Codes
10055 EDN381479,81479 Add to Order
EDNRB81479,81479
MITF81479,81479
PAX381479,81479
SNAI281479,81479
SOX1081479,81479
Test Code Test Copy Genes Total Price Panel CPT Code Gene CPT Codes Copy CPT Code STAT
10055 Genes x (6) $890 81479 81479 Add to Order

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.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

Targeted Testing

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

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Waardenburg syndrome (WS) is an auditory-pigmentary disorder characterized by congenital sensorineural hearing loss and pigmentary abnormalities of the hair, including a white forelock and pigmentary changes of the iris such as heterochromia. WS is classified into four main types depending on the clinical symptoms and is associated with causative mutations in several genes (Pingault et al. 2010; Read and Newton 1997).

WS I: Auditory-pigmentary abnormalities along with dystopia canthorum (lateral displacement of the inner canthi), caused by mutations in PAX3.

WS II: Auditory-pigmentary abnormalities without dystopia canthorum, caused by mutations in MITF, SNAI2 and SOX10.

WS III: Type I with musculo-skeletal abnormalities of the upper limb (Klein-Waardenburg syndrome) caused by mutations in PAX3.

WS IV: Type II with Hirschsprung disease (Waardenburg-Shah syndrome), caused by mutations in EDNRB, EDN3 and SOX10.

Genetics

WS is caused by mutations in genes (Pingault et al. 2010, Read and Newton 1997) that play a critical role in the formation of tissues and organs during embryonic development. They are active in neural crest cells and are involved in the formation of nerve tissue, bones in the face and skull (craniofacial bones), and also pigment-producing cells called melanocytes. Disruption or loss of any of these gene products results in the loss of melanocytes affecting the coloring of skin, hair, and eyes and also causes hearing loss, manifestations unique to Waardenburg syndrome. Variations of WS include limb and facial features (WSIII) and Hirschsprung disease (WSIV).

WS type I: Autosomal dominant syndrome caused by heterozygous mutations in PAX3 which include missense, nonsense, splicing, and in-frame deletions.

WS type IIA: Autosomal dominant syndrome caused by heterozygous mutations in MITF, which codes for the microphthalmia-associated transcription factor protein. MITF mutations are observed in 15% of individuals with WS2 (Read and Newton 1997) and include missense, truncating, splicing alterations along with deletions and insertions.

WS type IID: Autosomal recessive syndrome caused by defects in SNAI2 (snail family zinc finger 2), or SLUG as it is sometimes called. All SNAI2 causative WS mutations reported to date are large homozygous deletions (Sánchez-Martín et al. 2002); no point mutations have been identified.

WS type IIE: Autosomal dominant syndrome caused by heterozygous mutations in SOX10, which belongs to a family of genes called SRY(sex-determining region Y)-box genes. The types of causative mutations reported in SOX10 include missense, nonsense, splicing, and in-frame insertions.

WS type III: Caused by heterozygous or homozygous and compound heterozygous mutations in PAX3 suggesting autosomal dominant or recessive modes of inheritance. Causative mutations include missense, nonsense, splicing, and in-frame deletions.

WS type IVA: Autosomal recessive syndrome caused by mutations in EDNRB, which codes for the endothelin receptor type B protein. Rare cases of dominant transmission with incomplete penetrance have been reported. The types of causative mutations reported in EDNRB include missense and truncating variants.

WS type IVB: Autosomal recessive syndrome caused by mutations in EDN3, which codes for Endothelin 3 protein. Rare cases of dominant transmission with incomplete penetrance have been reported. The types of causative mutations reported in EDN3 include missense and truncating variants.

WS type IVC: Autosomal dominant syndrome caused by heterozygous mutations in SOX10, which belongs to a family of genes called SRY(sex-determining region Y)-box genes. The types of causative mutations reported in SOX10 include missense, nonsense, splicing, and in-frame insertions.

Testing Strategy

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).

Clinical Sensitivity - Sequencing with CNV

Mutations in multiple genes are known to cause Waardenburg Syndrome (WS) (Pingault et al. 2010).

WSI and III: Molecular genetic testing by sequencing of PAX3 detects more than 90% of disease-causing mutations. Partial and full gene deletions have also been documented.

WSII: Molecular genetic testing by sequencing of MITF detects more than 90% of disease-causing mutations. Since extensive studies evaluating the role of SNAI2 point mutations have not been carried out, the clinical sensitivity of our sequencing test for this gene is currently unknown. Partial and full gene deletions represent a significant proportion of SOX10 causative variants and have also been described for MITF and SNAI2.

WSIV: The clinical sensitivity of our sequencing assay for the END3, EDNRB and SOX10 genes for WSIV is currently unknown. Partial and full gene deletions have been documented for EDNRB and SOX10.

PAX3 is the only gene in which mutations are known to cause WS type 1 and type 3. Molecular genetic testing by deletion/duplication analysis of PAX3 detects about 6% of disease-causing mutations.

Indications for Test

Diagnostic criteria for Waardenburg syndrome has been proposed by the Waardenburg Consortium (Farrer et al. 1992). An individual must have two major criteria or one major plus two minor criteria to be considered affected.

Major Criteria: Congenital sensorineural hearing loss, white forelock, hair hypopigmentation; pigmentation abnormality of the iris: complete heterochromia iridum (irides of different color), partial/segmental heterochromia (two different colors in same iris, typically brown and blue) and hypoplastic blue irides, or brilliant blue irides. Dystopia canthorum, W index >1.95 is specific to WSI and is not observed in WSII and WSIV.

Minor Criteria: Skin hypopigmentation (congenital leukoderma), synophrys/medial eyebrow flare, broad/high nasal root, prominent columella, hypoplastic alae nasi, premature gray hair (age less than 30 years) and affected first-degree relative.

Diagnostic criteria for Waardenburg syndrome type IV (WSIV) includes the presence of Hirschsprung Disease along with any one of the criteria required for diagnosis of Waardenburg syndrome type II (WSII), including absence of dystopia canthorum.

Genes

Official Gene Symbol OMIM ID
EDN3 131242
EDNRB 131244
MITF 156845
PAX3 606597
SNAI2 602150
SOX10 602229
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Farrer LA, Grundfast KM, Amos J, Arnos KS, Asher JH, Beighton P, Diehl SR, Fex J, Foy C, Friedman TB, Greenberg J, Hoth C, et al. 1992. Waardenberg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: First report of the WS consortium. Am J Hum Genet 50: 902–913. PubMed ID: 1349198
  • Milunsky JM. 2011. Waardenburg Syndrome Type I. GeneReviews. PubMed ID: 20301703
  • Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. 2010. Review and update of mutations causing Waardenburg syndrome. Human Mutation 31: 391–406. PubMed ID: 20127975
  • Read AP, Newton VE. 1997. Waardenburg syndrome. Journal of medical genetics 34: 656–665. PubMed ID: 9279758
  • Sánchez-Martín M, Rodríguez-García A, Pérez-Losada J, Sagrera A, Read AP, Sánchez-García I. 2002. SLUG (SNAI2) deletions in patients with Waardenburg disease. Human molecular genetics 11: 3231–3236. PubMed ID: 12444107

Ordering/Specimens

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.

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

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