Etiology of syndromic and nonsyndromic sensorineural hearing loss

Hearing loss is the most common sensory deficit in humans. Advances in molecular biology and genetics have contributed substantially in the past decade to further our understanding of development, function, and pathology of the inner ear. Genetic tools such as positional cloning, analysis of molecular components of the mammalian cochlea, and mouse models have all contributed to accelerate the discovery of new deafness genes in the past 10 years. Among these, positional cloning has emerged as the most powerful strategy. In this technique, individuals of a sufficiently large family, in which the disease is segregating, are genotyped with polymorphic markers evenly distributed across the chromosomes. These markers are a uniquely identifiable segment of DNA. Through linkage analysis, a statistical genetic method, the disease gene can then be localized to a specific region on a specific chromosome. With the availability of sequence of the human genome, the database can be searched for genes expressed in this region; because of their location in the mapped region, they are identified as candidate genes potentially responsible for the disease seen in the family. The final step is to identify a mutation that segregates with the disease in the family. Hereditary deafness is genetically a highly heterogeneous disease with many different genes responsible for auditory dysfunction. To complicate things further, different mutations in one gene can cause variable phenotype. With new genes cloned monthly, we are still only at the beginning of putting together the complex puzzle of the hearing sense. In the future, functional and developmental studies based on today's molecular and genetic findings will be needed. This article summarizes our current knowledge in the field of molecular genetics for the most common syndromes associated with hearing loss, as well as for nonsyndromic hearing impairment.