Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis
Sophie Boucher, Fabienne Wong Jun Tai, Sedigheh Delmaghani, Andrea Lelli, Amrit Singh‐Estivalet, Typhaine Dupont, Magali Niasme-Grare, Vincent Michel, Nicolas Wolff, Amel Bahloul, Yosra Bouyacoub, D. Bouccara, Bernard Fraysse, Olivier Déguine, Lionel Collet, Hung Thaï-Van, E. Ionescu, Jean-Louis Kémény, Fabrice Giraudet, Jean‐Pierre Lavieille, Arnaud Devèze, Anne-Laure Roudevitch-Pujol, C. Vincent, Christian Renard, V. Franco‐Vidal, Claire Thibult-Apt, Vincent Darrouzet, Éric Bizaguet, Arnaud Coëz, Hugues Aschard, Nicolas Michalski, G. Lefèvre, Anne Aubois, Paul Avan, Crystel Bonnet, Christine Petit
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.