Waardenburg Syndrome Panel

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.

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.

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.

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. 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).