DFNA25, a novel locus for dominant, nonsyndromic, high frequency sensorineural hearing impairment. C.C. Greene, P.M. McMillan, S.E. Barker, M.M. Lesperance. Otolaryngology-Head & Neck Surgery, University of Michigan, Ann Arbor MI.

   This is a study of a family of Czech descent from the midwestern United States with nonsyndromic dominant, progressive, high frequency sensorineural hearing impairment. Twenty-three of the patients studied are affected as compared to the 90th percentile for sex and age as measured in an unselected population (Robinson 1988). The youngest affected member was diagnosed at birth and the onset of hearing impairment for all affected members usually occurred in the first 2 decades of life. An estimate of the ability to detect linkage was calculated using the statistical software program SLINK (Ott, 1989). Ninety-nine-point-five percent of the 200 replicates of the pedigree generated by SLINK yielded a logarithm-of-odds (LOD) score over 3.0 (average maximum LOD score 9.75). Genotyping was performed using the polymerase chain reaction with radiolabeled primers and polyacrylamide gel electrophoresis. Linkage to known dominant loci for hereditary sensorineural hearing impairment was excluded by analyzing genotype data with the statistical software program MLINK (Ott, 1989). DNA from 50 patients (16 affected) informative for linkage analysis was then submitted to the Mammalian Genotyping Service for high-throughput genotyping across the entire genome. The genotype data for all markers was analyzed with MLINK. Linkage was detected to chromosome 12q21-q24 by analysis of a polymorphic marker within the phenylalanine hydroxylase (PAH) gene (LOD score of 4.02 at q = 0.1). Further genotyping of nearby markers and haplotype analysis revealed that the gene responsible for the hearing impairment in this family (DFNA25) maps to a 30 cm region defined by affected recombinants at D12S1052 and D12S1597. The region of human chromosome 12q21-24 has homology with a region of mouse chromosome 10. We are in the process of further narrowing the genetic interval by testing additional markers in the region. Haplotype analysis of these data and a discussion of candidate genes will be presented. (Supported by 1K08 DC 00161-01A1 and a grant from the Mammalian Genotyping Service of the National Heart, Lung and Blood Institute).