Investigation of the genetic cause of hereditary hearing loss in three large deaf, consanguineous Newfoundland families

• Main Author: Cooke, Sandra M.
• Format: Thesis
• Language: English
• Published: Memorial University of Newfoundland 2008
• Subjects: Newfoundland
• Online Access: https://research.library.mun.ca/9201/; https://research.library.mun.ca/9201/1/Cooke_SandraM.pdf

Three large Newfoundland families segregating with autosomal recessive hearing loss were studied in this thesis project: Family A, Family B and Family 41. Previous work on Family A identified a pathogenic mutation in the deafness gene PCDH15 which explained deafness in five family members homozygous for the mutation but did not fully explain the deafness in five other family members heterozygous for the mutation. A second deafness gene, CDH23 is located very close to the PCDH15 on chromosome 10. Single mutations in these two genes are known to cause both Ushers syndrome and non-syndromic deafness. All 69 exons and all intron/exons boundaries in CDH23 were sequenced in four Family A members which identified 45 SNPs. Only eight SNPs were potentially pathogenic because they were found in the coding region and they were polymorphic. However, no one variant of the eight SNPs segregated exclusively with deafness; in addition, all eight SNPs were previously reported as non-pathogenic. It was concluded that CDH23 does not contribute to the deafness in Family A. Previous work on Family B determined the familial deafness was due to mutations in TMPRSS3:c.782+3de1GAG, a novel mutation, and c.207de1C, a known mutation. Informative markers and intrageneic SNPs with the TMPRSS3 gene were used to construct and characterize the two TMPRSS3 mutation haplotypes. A single copy of the novel TMPRSS3 mutation (c.782+3de1GAG) was found in a deaf boy in Family 41 and his hearing mother and their TMPRSS3 haplotypes were constructed. It was found that carriers of the TMPRSS3 c.782+3delGAG mutation in Family B and Family 41 shared a haplotype spanning 10.1Mb. Since the two families are not known to be related, the TMPRSS3 c.782+3de1GAG was designated a founder mutation.