Waardenburg Syndrome Types I and III via the PAX3 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 I: The hearing loss observed in approximately 60% of affected individuals is congenital, typically non-progressive, either unilateral or bilateral, and sensorineural. The majority of individuals with WS1 have either a white forelock or early graying of the scalp hair before age 30 years. The classic white forelock observed in approximately 45% of individuals is the most common hair pigmentation anomaly seen in WS1. Affected individuals may have complete heterochromia iridium, partial/segmental heterochromia, or hypoplastic or brilliant blue irides. Congenital leukoderma is frequently seen on the face, trunk, or limbs (Milunsky et al, Gene Reviews). WS III: The musculo-skeletal abnormalities present with flexion contractures and muscle hypoplasia of the upper limb with a broad range of severity. Other signs such as campylodactly may be associated.

WS type 1 is an autosomal dominant syndrome caused by heterozygous mutations in PAX3, while WS type 3 can be caused by heterozygous or homozygous mutations in PAX3 suggesting an autosomal dominant or recessive mode of inheritance. PAX3 belongs to a family of homeobox transcription factor genes that play a critical role in the formation of tissues and organs during embryonic development. The PAX3 protein directs the activity of other genes that signal neural crest cells to form specialized tissues or cell types such as some nerve tissue, bones in the face and skull (craniofacial bones), and pigment-producing cells called melanocytes. Disruption or loss of the PAX3 protein results in the manifestation of the limb and facial features that are unique to Waardenburg syndrome, types I and III. Mutations in PAX3 are also known to be causative for craniofacial-deafness-hand syndrome. The types of causative mutations reported in PAX3 include missense, nonsense, splicing, and inframe deletions.

PAX3 is the only gene in which mutations are known to cause WS type 1 and type 3; molecular genetic testing by sequencing of PAX3 detects more than 90% of disease-causing mutations.

Molecular genetic testing by deletion/duplication analysis of PAX3 detects about 6% of disease-causing mutations.

This test provides full coverage of all coding exons of the PAX3 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).