Waardenburg syndrome (WS) is a series of auditory-pigmentary disorders inherited 
in an autosomal dominant manner. In most patients, WS2 results from mutations in 
the MITF gene. MITF encodes a basic helix-loop-helix transcription factor that 
activates transcription of tyrosinase and other melanocyte proteins. The 
clinical presentation of WS is highly variable, and we believe that Tietz 
syndrome and WS2 with ocular albinism (OA) are likely two variations of WS2 due 
to the presence of modifiers. One family with a molecular diagnosis of WS2 
co-segregating with OA has previously been reported. A digenic mutation 
mechanism including both a MITF mutation and the TYR(R402Q) hypomorphic allele 
was proposed to be the cause of OA in this family. Here, we present a second WS2 
family with OA and provide evidence suggesting the TYR(R402Q) allele does not 
cause OA in this family. We hypothesize the presence of a novel OCA3 mutation 
together with the MITF del p.R217 mutation account for the OA phenotype in this 
family. Since MITF is a transcription factor for pigmentation genes, a mutation 
in MITF plus a heterozygous mutation in OCA3 together provide an adverse effect 
crossing a quantitative threshold; therefore, WS2 with OA occurs. We have 
hypothesized previously that the clinical spectrum and mutation mechanism of OCA 
depend on the pigmentation threshold of an affected individual. This unique 
family has provided further evidence supporting this hypothesis. We suggest that 
by studying OCA patients alongside WS patients with various pigmentation 
profiles we can facilitate further understanding of the pigmentation pathway.