Investigation of genetic cause of hearing loss in 28 autosomal dominant families within the Newfoundland founder population

The purpose of this study was to determine the genetic cause of hearing loss in 28 Newfoundland families with Autosomal Dominant hearing loss. AD hearing loss is highly genetically heterogeneous, and is mainly associated with a late onset, progressive phenotype. After a comprehensive literature search, genotype-phenotype evaluations, and a functional candidate gene approach, all 28 probands were sequenced to identify mutations in four genes known to cause autosomal dominant hearing loss, COCH, KCNQ4, TECTA, and MYO1A. First, a known Dutch founder mutation within exon 4 of COCH, c.151 C>CT, was found in a Newfoundland proband of Family 2094. All affected family members (n=7) shared this mutation, while unaffected members did not. This is only the second family found to harbor this mutation outside of Europe. This mutation is strongly associated with severe vestibular decline. Affected Family 2094 members carrying the mutation do present vestibular decline in the form of vertigo and balance difficulties. As this mutation is considered to be a Dutch founder mutation, DNA samples from a Dutch p.P51P/S family were genotyped and compared with Family 2094 genotypes. Fragment analysis confirmed haplotype sharing of five markers closely bordering the c.151 C>CT mutation between Newfoundland and Dutch mutation carriers. Second, a novel 3bp deletion in exon 5 of KCNQ4 was found in 13 affected members of Family 2071. While the mutation was not seen in four other affected family members, audiology test results suggest that these four individuals are phenocopies. Sequencing of the full KCNQ4 gene was done in all individuals, to rule out another mutation on the same gene. Further investigation, through the construction of an intragenic haplotype, did not point to any further hearing loss associated variants within KCNQ4, and confirmed that all deletion carriers share a common hearing loss haplotype and deletion. Third, a nonsense mutation was found in exon 4 of MYO1A in the proband of Newfoundland Family 2102. This is a C→T nucleotide substitution (c.2435 C>CT) that causes a change (p.R93X) in the motor domain of myosin 1A. Of four individuals in Family 2102, three were found to carry the p.R93X mutation, while one unaffected sibling was not. This mutation has been reported once before in a small Italian family. No mutations were discovered in the TECTA gene. When each of the causative mutations in COCH, KCNQ4, and MYO1A was detected, additional Newfoundland hearing loss probands were screened, to rule out the possibility of a founder mutation. In no case were additional mutation carriers identified. While no founder mutations were discovered in this study, the genetic cause of hearing loss was identified in three families.