Waardenburg Syndrome Types IIE and IVC via the SOX10 Gene

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 4 main types depending on the clinical symptoms and has causative mutations in different genes (Pingault et al. 2010).

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 EDN3, EDNRB and SOX10.

WS type II is typified by sensorineural hearing loss and heterochromia iridumis observed in approximately 77% and 47% of affected individuals respectively, and is much more common than WS type I (Liu et al. 1995). Dystopia canthorum is NOT observed in WS II. WSII Individuals with mutations in SOX10 also show neurologic abnormalities, including mental impairment, myelination defects, and ataxia.

WS IV: Characterized by the presence of Hirschsprung disease in patients with Waardenburg syndrome type 2 with no dystopia canthorum. The majority of individuals have the classic white forelock and heterochromia iridium along with variable manifestations of sensorineural deafness and Hirschsprung disease.

WS type IIE and type IVC are autosomal dominant syndromes caused by heterozygous mutations in SOX10, which belongs to a family of genes called SRY(sex-determining region Y)-box genes. These genes play a critical role in the formation of tissues and organs during embryonic development. The SOX10 protein is active in neural crest cells and plays an essential role in the formation of nerves in the large intestine and melanocytes. Disruption or loss of the SOX10 protein results in the loss of enteric nerve cells that are critical to intestinal development, resulting in Hirschsprung disease. Similarly, a lack of melanocytes due to loss of the SOX10 protein also affects the coloring of skin, hair, and eyes and causes hearing loss, which are unique to Waardenburg syndrome. SOX10 point mutations (Iso et al. 2008) and deletions have been described in about 15% of individuals with WS2 and 40-50% of cases of WS4 (Bondurand et al. 2007).

Mutations in SOX10 are also known to be causative for PCWH (peripheral demyelinating neuropathy, central demyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease).

About 30 mutations have been identified in SOX10 associated with WSIIE, WSIVC and PCWH. Since large deletions have not been described for SOX10, we believe that our sequencing test will be able to identify the great majority of mutations.

This test provides full coverage of all coding exons of the SOX10 gene 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 full 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).