Positional Cloning of Deafness Genes

The identification of the majority of the known causative genes involved in nonsyndromic sensorineural hearing loss (NSHL) started with linkage analysis as part of a positional cloning procedure. The human and mouse genome projects in combination with technical developments on genotyping, transcriptomics, proteomics, and the creation of animal models have greatly enhanced the speed of disease gene identification. In the present chapter, we first discuss the possibilities for exclusion of known NSHL loci and genes. Subsequently, methods are described to determine the genomic regions that contain the genetic defects. These include linkage analysis with genotyping and statistical evaluation and the determination of copy number variations. In the case of a large genomic region, candidate genes are selected and prioritized using gene expression analysis, protein network data, and phenotypes of animal models. A number of algorithms are described to automate the process of candidate gene selection. The novel high-throughput sequencing techniques might make gene selection and prioritization unnecessary in the near future. Once genetic variants are identified, questions on pathogenicity need to be addressed, which is the topic of the last section of this chapter.