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This review presents two genes illustrative of this concept that have varied expression pattern such that they may produce either syndromic or nonsyndromic hearing loss. One of these genes, cadherin 23, produces a spectrum of phenotypic traits, including presbycusis, nonsyndromic prelingual hearing loss (DFNB12), and syndromic hearing loss as part of Usher syndrome (Usher 1D). Missense mutations in <jats:italic>CDH23<\/jats:italic> have been associated with presbycusis and DFNB12, whereas null alleles cause the majority of Usher 1D. Modifier gene products that interact with cadherin 23 also affect the phenotypic spectrum. Similarly, allelsim in the gene encoding wolframin (<jats:italic>WFS1<\/jats:italic>) causes either a nonsyndromic dominant low\u2010frequency hearing loss (DFNA6\/14\/38) or Wolfram syndrome. Missense mutations within a defined region are associated with DFNA6\/14\/38, while more severe mutations spanning <jats:italic>WFS1<\/jats:italic> are found in Wolfram syndrome patients. The phenotypic spectrum of Wolfram syndrome is also hypothesized to be influenced by modifier genes products. These studies provide increasing evidence for the importance of modifier genes in elucidating the functional pathways of primary hearing loss genes. Characterizing modifier genes may result in better treatment options for patients with hearing loss and define new diagnostic and therapeutic targets. Anat Rec Part A, 2006. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ar.a.20297","type":"journal-article","created":{"date-parts":[[2006,3,20]],"date-time":"2006-03-20T18:18:55Z","timestamp":1142878735000},"page":"370-381","source":"Crossref","is-referenced-by-count":27,"title":["Genetics of hearing loss: Allelism and modifier genes produce a phenotypic continuum"],"prefix":"10.1002","volume":"288A","author":[{"given":"Richard K.","family":"Mchugh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rick 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