Waardenburg syndrome is an excellent example of genetic heterogeneity as types 1 and 3 (193500, 148820), 2 (193510), and 4 (277580) are all caused by mutations in different genes.
Type 2 described here is a genetically heterogeneous autosomal dominant disorder. WS2A is caused by a mutation in MITF (microphthalmia-associated transcription factor) (3p14.1-p12.3). This is the same disorder described as 'Albinism, ocular, with sensorineural deafness' in OMIM (103470) (WS2-OA).
A locus at 1p21-p13.3 is associated with WS2B (600193) and WS2C (606662) maps to 8p23. In addition, homozygous SNAI2 mutations at 8q11 have been found in several patients with WS2D (608890) suggesting autosomal recessive inheritance but the normal parents were not studied. Recent evidence suggests that SOX10 mutations can also play a role via MITF promoter modulation (WS2E) (611584).
Type 4 is also the result of mutations in at last three genes.
A child has been reported who was doubly heterozygous for mutations involving both MITF and PAX3. Hypopigmentation in the scalp hair, eyebrows and eyelashes was more severe than usually seen in patients with single mutations. In addition the face showed marked patchy pigmentation. One parent contributed the MITF mutation and the other added the mutation in PAX3.