PRESYMPTOMATIC DIAGNOSIS OF NONSYNDROMIC HEARING-LOSS BY GENOTYPING

Background: Nonsyndromic hearing loss (NSHL) is the most common type o f hereditary hearing impairment (HHI). It is genetically heterogeneous , and although the exact number of genes is not known, 38 loci have be en identified. By cloning the relevant genes and studying the function of the encoded proteins at the molecular level, it may be possible to impart the habitation of persons at risk for HHI. Currently, for sele ct families, presymptomatic diagnosis of NSHL by genotyping is possibl e. Objective: To provide presymptomatic diagnosis of HHI to individual s in select families who have participated in linkage studies. Design: In 2 large families with autosomal dominant HHI, genes for NSHL were mapped to chromosomes 6 (DFNA10) and 19 (DFNA4). In each family, the p henotype is one of progressive sensorineural hearing loss that begins in the individual's mid-30s and progresses to a severe-to-profound los s requiring amplification. Presymptomatic diagnosis was requested by, and provided to, 19 at-risk persons in these kindreds. Results: By rec onstructing haplotypes through the use of short tandem repeat polymorp hisms tightly linked to the disease gene, risk calculations and geneti c counseling were provided to these persons. Conclusions: By simple Me ndelian genetics, the risk of inheriting a fully penetrant autosomal d ominant NSHL gene from a single affected parent is 50% for each offspr ing. However, by reconstructing haplotypes in families in which an HHI gene has been localized, this risk can be changed substantially.