Denise Yan and Xue-Zhong Liu Pages 269 - 278 ( 10 )
Lack of penetrance and variability of expression are common findings in nonsyndromic hearing loss with autosomal dominant mode of inheritance, but are also seen with recessive inheritance. Now we know that genotype cannot necessarily predict phenotype due to the complexity of the genome, the proteome interacting with the transcriptome, and the dynamically coupled systems that are involved. The contribution of genetic background to phenotypic diversity reflects the additive and interactive (epistasis) effects of multiple genes. Because, individual genes do not act alone but rather in concert with many other genes, it is not surprising that, modifier genes are common source of phenotypic variation in human populations. They can affect the phenotypic outcome of a given genotype by interacting in the same or in a parallel biological pathway as the disease gene. These modifier genes modulate penetrance, dominance, pleiotropy or expressivity in individuals with Mendelian traits and can also be exerted by influencing the severity, the penetrance, the age of onset and the progression of a disease. In this review, we focus on modifier genes that specifically affect hearing loss phenotypes in humans as well as those described in mice. We also include examples of digenic inheritance of deafness, because additive or interactive effects can also result from interaction between two mutant genes.
Deafness, heredity, phenotypic variation, heterogeneity, allelism, modifier genes, digenic inheritance, inbred mouse strain
Department of Otolaryngology (D-48), University of Miami, 1666 NW 12th Avenue, Miami, Florida 33136, USA.