Waardenburg Syndrome Type IID via the SNAI2 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 iridum is 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. Other clinical manifestations such as the classic white forelock are more common in WS1.

WS type IID is an autosomal recessive syndrome caused by homozygous deletions of the SNAI2 gene. The snail family zinc finger 2 (SNAI2), or SLUG as it is sometimes called, is a transcription factor that plays a role in formation of tissues, particularly the neural crest during embryonic development (Perez-Mancera et al. 2007). Lack of snail 2 may disrupt the development of melanocytes in certain areas of the skin, hair, eyes, and inner ear, leading to hearing loss and the patchy loss of pigmentation that are characteristic features of Waardenburg syndrome, type II. Limited studies evaluating the role of SNAI2 mutations in Waardenburg syndrome suggest that it plays a minor role in WS2 (Pingault et al. 2010). Mutations identified so far are solely homozygous deletions (Sánchez-Martín et al. 2002), no point mutations have been identified. Mutations in SNAI2 are also known to be causative for Piebaldism (Sánchez-Martín et al. 2003).

Limited studies identify deletions of SNAI2 to be responsible for WS2 (Sánchez-Martín et al. 2002). Since extensive studies evaluating the role of SNAI2 point mutations have not been carried out, the clinical sensitivity of our sequencing test is currently unknown.

This test provides full coverage of all coding exons of the SNAI2 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).