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Conclusions: There could be another candidate gene in DFNA2, which could be responsible for the hearing loss phenotype. Objective: We collected a four-generation family from the southern part of China with autosomal dominant sensorineural hearing impairment. In order to identify the responsible pathogenic mutations in this family, we set out to identify the locus and to sequentially analyze the candidate genes in the identified region. Methods: After family ascertainment and clinical analysis, exclusive analysis was performed. Then a genome-wide scan was performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM). Fine-mapping markers were genotyped to identify the locus. Finally, we performed haplotype analyses and candidate gene DNA sequencing for the family. Results: The known genetic loci and genes were not associated with our family. The genome-wide scan and haplotype analyses traced the disease to chromosome 1p34.2-p34.3 with maximum multi-point LOD score of 3.2, which overlaps with DFNA2. We failed to identify any of the known or novel variants within KCNQ4, a voltage-gated potassium channel gene, and GJB3, a gene that encodes the gap junction protein connexin 31, which were the cloned deafness genes in DFNA2. [ABSTRACT FROM AUTHOR]

Conclusions: Analysis of the complete mtDNA genome and X-linkage of this five-generation Chinese family revealed that the 1555A > G mutation may lead to deafness. Objectives: Mutations in mitochondrial DNA (mtDNA) have been found to be associated with sensorineural hearing loss. However, the variable clinical phenotype and incomplete penetrance of mtDNA 1555A > G-induced hearing loss complicate our understanding of this mutation. We aimed to identify whether nuclear genes, mitochondrial haplotypes/variants, and a possible threshold effect are involved in its manifestation in the pedigree. Methods: We performed clinical, genetic, and X-linkage analysis of a five-generation Chinese family in which all the affected individuals were male. Results: Clinical evaluation revealed that affected individuals with or without aminoglycoside exposure developed hearing loss extending gradually from 8000 Hz to 4000 Hz and then to 1000 Hz. Using X-linkage analysis and sequencing, we detected an identical homoplasmic 1555A > G mutation in nine individuals, and a previously unreported variant 14163C > T in mtDNA. The new variant 14163C > T coexisted with the 1555A > G mutation in six affected subjects of our pedigree. The previously unreported variant 14163C > T and aminoglycoside exposure may synergize the development of this deafness. [ABSTRACT FROM AUTHOR]