Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis

Heterozygote MESH: Mutation MESH: Mitochondria MESH: Age of Onset MESH: Deafness Deafness Cohort Studies Mice 03 medical and health sciences MESH: Presbycusis MESH: Whole Exome Sequencing Exome Sequencing Animals Humans MESH: Animals Age of Onset ultrarare variants MESH: Cohort Studies MESH: Mice MESH: Heterozygote Genes, Dominant MESH: Age Factors [SDV.GEN]Life Sciences [q-bio]/Genetics 0303 health sciences MESH: Humans monogenic disorder Age Factors Membrane Proteins Tmc1 Presbycusis MESH: Case-Control Studies Mitochondria 3. Good health age-related hearing loss MicroRNAs Case-Control Studies Mutation MESH: Membrane Proteins MESH: Genes, Dominant presbycusis MESH: MicroRNAs
DOI: 10.1073/pnas.2010782117 Publication Date: 2020-11-24T02:42:10Z
ABSTRACT
Significance Presbycusis, or age-related hearing loss, is a major public health issue and the principal potentially modifiable risk factor for dementia. It is caused by environmental factors and largely uncharacterized genetic factors. We compared DNA sequences across genomic coding regions between familial or sporadic cases of severe presbycusis and controls with normal hearing. The frequency of ultrarare predicted pathogenic variants in genes known to cause dominant early-onset forms of deafness was significantly higher in both familial and sporadic cases than in controls. Pathogenicity of many of these variants was established with complementary analyses. Ultrarare variants have a large effect size and are known to cause monogenic disorders. These findings open up possibilities for curing these forms of presbycusis by gene therapy.
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