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
AUTHORS (36)
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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CITATIONS (43)
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