Waardenburg Syndrome Type IIA via the MITF 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. Other clinical manifestations such as the classic white forelock are more common in WS1.

WS type II is an autosomal dominant syndrome caused by heterozygous mutations in the MITF gene. MITF, the microphthalmia-associated transcription factor, helps control the development and function of pigment-producing cells called melanocytes, which produce the pigment melanin, contributing to hair, eye, and skin color. Melanocytes are also found in the inner ear and play an important role in hearing. Mutations in MITF alter protein dimerization impacting melanocyte development (Widlund and Fisher, 2003). Shortage of melanocytes results in hypopigmentation and hearing loss characteristic of Waardenburg syndrome. It is estimated that MITF mutations are observed in 15% of individuals with WS2 (Read and Newton, 1997). Mutations include missense, truncating, splicing alterations along with deletions and insertions. Digenic inheritance of WS with ocular albinism has been suggested (Chiang et al., 2009). Mutations in MITF are also known to be causative for Tietz syndrome (Smith et al., 2000).

It is estimated that MITF mutations are observed in 15% of individuals with WS2 (Read and Newton, 1997). Molecular genetic testing by sequencing of MITF detects more than 90% of disease-causing mutations.

This test provides full coverage of all coding exons of the MITF gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.