Genetics of hearing loss: Allelism and modifier genes produce a phenotypic continuum

Abstract

Recent genetic and genomic studies have greatly advanced our knowledge of the structure and function of genes involved in hearing loss. We are starting to recognize, however, that many of these genes do not appear to follow traditional Mendelian expression patterns and are subject to the effects of allelism and modifier genes. 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 CDH23 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 (WFS1) causes either a nonsyndromic dominant low-frequency 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 WFS1 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 tar- Severe hearing impairment affects 1 in 1,000 newborns and a further 1 in 1,000 children suffer hearing impairment significant enough to affect speech and language development (Fortnum et al., 2001). Approximately 50% of prelingual hearing loss is attributed to hereditary factors. Hereditary hearing loss is divided by clinical phenotype into syndromic, in which hearing loss is concurrent with malformation of other organ systems, and nonsyndromic, in which hearing loss is the only disease phenotype. Syndromic and nonsyndromic hearing losses are classified by modes of inheritance including autosomal dominant, autosomal recessive, X-linked, and mitochondrial or maternally inherited. Nonsyndromic forms of hearing loss have systematic names based on mode of inheritance including DFNA for autosomal dominant, DFNB for autosomal recessive, and DFN for both X-linked and mitochondrial. To date, over 80 genes have been identified in hearing loss that divide almost evenly between syndromic and nonsyndromic forms (Van Camp et al.,

Mutations in LOXHD1 Gene Cause Various Types and Severities of Hearing Loss

“…The genotype-phenotype correlation in LOXHD1 is still unclear. The differences of phenotype in each affected individual might be the result of the nature of the mutations, the location at the gene, and affected by genetic modifier [14]. …”

Mutations of GJB2 encoding connexin 26 contribute to non-syndromic moderate and severe hearing loss in Pakistan

“…The association of p.W24X and p.W77X mutations with both profound and less severe phenotype of hearing loss suggests the effect of modifier genes that lead to variation in hearing thresholds [13] and is similar to that suspected for c.35delG related deafness. So far, for lack of a sufficiently large family, it has not been possible to map a genetic modifier, which reduces severity of hearing loss caused by GJB2 mutations [14].…”

A deleterious mutation in the LOXHD1 gene causes autosomal recessive hearing loss in Ashkenazi Jews

“…In contrast to the progressive nature of the NSHL in the reported Iranian patients [Grillet et al, 2009] in our cohort, patients from both families had a non-progressive congenital NSHL. The variable age of onset and clinical course among patients with hearing loss caused by mutations in the same gene, is well documented; it might be the result of the nature of the mutation or its location and could depend on modifier genes [McHugh and Friedman, 2006]. Mutations in the GJB2 and GJB6 genes are the most prevalent causes for ARNSHL among Ashkenazi Jews.…”