A novel mutation in COCH-implications for genotype-phenotype correlations in DFNA9 hearing loss

Abstract

Objectives/hypothesis: To determine the cause of autosomal dominant hearing loss segregating in an American family.

Study design: Family study.

Methods: Otologic and audiometric examination was performed on affected family members. Genome wide parametric multipoint linkage mapping using a dominant model was performed with Affymetrix 50K GeneChip data. Direct sequencing was used to confirm the causative mutation.

Results: In American family 467, segregating autosomal dominant nonsyndromic hearing loss, a novel heterozygous missense mutation (c.362T>C; p.F121S) was identified in the COCH gene. This mutation was also associated with vestibular dysfunction typical of other DFNA9 families. However, affected family members also exhibited memory loss and night blindness.

Conclusions: The novel COCH mutation affects the functionally important limulus factor C, Coch-5b2 and Lgl1 domain where most DFNA9 mutations have been localized. The onset of the hearing loss, in the 2nd or 3rd decade of life, is earlier than in most DFNA9 families. The progression of hearing loss and vestibular dysfunction in the American family is typical of other DFNA9 families with mutations in this domain. Memory loss and night blindness have not been previously reported in DFNA9 families.

Figure 1

Pedigree and audiograms of American family 467. A. Family 467; genotypes for individuals carrying the c.362T>C mutation are shown. Open symbols = unaffected; filled symbols = affected; diagonal line = deceased. B. Audiograms of affected members of family 467. Age at time of audiogram are shown in brackets.

Figure 1

Pedigree and audiograms of American family 467. A. Family 467; genotypes for individuals carrying the c.362T>C mutation are shown. Open symbols = unaffected; filled symbols = affected; diagonal line = deceased. B. Audiograms of affected members of family 467. Age at time of audiogram are shown in brackets.

Figure 2

Linkage mapping results for family 467. A. Graph showing LOD score for the region on chromosome 14. LOD scores of 0 (blue line) and 3 (pink line) are indicated. B. Haplotype analysis results of family 467. Affymetrix SNP markers are shown.

Figure 2

Linkage mapping results for family 467. A. Graph showing LOD score for the region on chromosome 14. LOD scores of 0 (blue line) and 3 (pink line) are indicated. B. Haplotype analysis results of family 467. Affymetrix SNP markers are shown.

Figure 3

Mutation analysis results for family 467. A. Novel COCH mutation in family 467. B. Multisequence alignment of the cochlin protein showing high conservation of the F121 residue across species.