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

• DOI: 10.1073/pnas.2010782117
• Publication Date: 2020-11-24T02:42:10Z
• Authors: Sophie Boucher; Fabienne Wong Jun...; Sedigheh Delmaghani; Andrea Lelli; Amrit Singh-Estiv...; Typhaine Dupont; Magali Niasme-Grare; Vincent Michel; Nicolas Wolff; Amel Bahloul; Yosra Bouyacoub; Didier Bouccara; Bernard Fraysse; Olivier Deguine; Lionel Collet; Hung Thai-Van; Eugen Ionescu; Jean-Louis Kemeny; Fabrice Giraudet; Jean-Pierre Lavie...; Arnaud Devèze; Anne-Laure Roudev...; Christophe Vincent; Christian Renard; Valérie Franco-Vidal; Claire Thibult-Apt; Vincent Darrouzet; Eric Bizaguet; Arnaud Coez; Hugues Aschard; Nicolas Michalski; Gaëlle M. Lefevre; Anne Aubois; Paul Avan; Crystel Bonnet; Christine Petit
• Keywords: 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

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.