While modifier genes were first described in Drosophila over 80 years ago [1], in humans the effects of modifier genes on hereditary hearing loss have only been reported recently [2, 3]. The existence of such modifiers is suggested by the observation that deaf siblings can differ significantly in the severity of hearing loss that is presumably caused by identical mutations of the same gene [4, 5]. The intra-familial variability of hereditary hearing impairment may be attributable to modifying genetic loci, environmental effects and/or stochastic variation [2, 6].

In other mammalian systems such as the mouse, genetic modifiers of hereditary deafness have already been demonstrated: Homozygous tubby (tub) mice are obese and have hearing loss associated with degeneration of hair cells and spiral ganglion cells [7]. However, a dominant allele at the moth1 locus prevents hearing loss in homozygous tubby mice [8]. Similarly, a dominant allele of another modifier locus, mdfw, prevents hearing loss in deaf-waddler (dfw) heterozygotes [9]. A third mouse model provides insight into the molecular mechanism of modification. Heterozygosity for a knockout allele of the thyroid hormone receptor-2 splice isoform (Thratm2) suppresses deafness and thyroid dysfunction in homozygous thyroid hormone receptor beta (Thrb) knockout mice [10]. Expression of the Thra-1 splice variant is upregulated in Thratm2/+ mice, and the authors postulated that this overexpression rescues the deafness phenotype due to functional redundancy