Ultrarare heterozygous pathogenic variants ...
Type de document :
Article dans une revue scientifique: Article original
DOI :
PMID :
URL permanente :
Titre :
Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis.
Auteur(s) :
Boucher, S. [Auteur]
Wong Jun Tai, F. [Auteur]
Delmaghani, S. [Auteur]
Lelli, A. [Auteur]
Singh-Estivalet, A. [Auteur]
Dupont, T. [Auteur]
Niasme-Grare, M. [Auteur]
Michel, V. [Auteur]
Wolff, N. [Auteur]
Bahloul, A. [Auteur]
Bouyacoub, Y. [Auteur]
Bouccara, D. [Auteur]
Fraysse, B. [Auteur]
Deguine, O. [Auteur]
Collet, L. [Auteur]
Thai-Van, H. [Auteur]
Ionescu, E. [Auteur]
Kemeny, J. L. [Auteur]
Giraudet, F. [Auteur]
Lavieille, J. P. [Auteur]
Devèze, A. [Auteur]
Roudevitch-Pujol, A. L. [Auteur]
Vincent, Christophe [Auteur]
Advanced Drug Delivery Systems (ADDS) - U1008
Renard, C. [Auteur]
Franco-Vidal, V. [Auteur]
Thibult-Apt, C. [Auteur]
Darrouzet, V. [Auteur]
Bizaguet, E. [Auteur]
Coez, A. [Auteur]
Aschard, H. [Auteur]
Michalski, N. [Auteur]
Lefevre, G. M. [Auteur]
Aubois, A. [Auteur]
Avan, P. [Auteur]
Bonnet, C. [Auteur]
Petit, C. [Auteur]
Wong Jun Tai, F. [Auteur]
Delmaghani, S. [Auteur]
Lelli, A. [Auteur]
Singh-Estivalet, A. [Auteur]
Dupont, T. [Auteur]
Niasme-Grare, M. [Auteur]
Michel, V. [Auteur]
Wolff, N. [Auteur]
Bahloul, A. [Auteur]
Bouyacoub, Y. [Auteur]
Bouccara, D. [Auteur]
Fraysse, B. [Auteur]
Deguine, O. [Auteur]
Collet, L. [Auteur]
Thai-Van, H. [Auteur]
Ionescu, E. [Auteur]
Kemeny, J. L. [Auteur]
Giraudet, F. [Auteur]
Lavieille, J. P. [Auteur]
Devèze, A. [Auteur]
Roudevitch-Pujol, A. L. [Auteur]
Vincent, Christophe [Auteur]
Advanced Drug Delivery Systems (ADDS) - U1008
Renard, C. [Auteur]
Franco-Vidal, V. [Auteur]
Thibult-Apt, C. [Auteur]
Darrouzet, V. [Auteur]
Bizaguet, E. [Auteur]
Coez, A. [Auteur]
Aschard, H. [Auteur]
Michalski, N. [Auteur]
Lefevre, G. M. [Auteur]
Aubois, A. [Auteur]
Avan, P. [Auteur]
Bonnet, C. [Auteur]
Petit, C. [Auteur]
Titre de la revue :
Proceedings of the National Academy of Sciences of the United States of America
Nom court de la revue :
Proc Natl Acad Sci U S A
Date de publication :
2020-11-25
ISSN :
1091-6490
Mot(s)-clé(s) :
presbycusis
age-related hearing loss
monogenic disorder
ultrarare variants
Tmc1
age-related hearing loss
monogenic disorder
ultrarare variants
Tmc1
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare ...
Lire la suite >Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls ( P = 0.001); half were previously unknown (AF < 0.000002). MYO6 , MYO7A , PTPRQ , and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1 N321I/+ mice, carrying the TMC1 :p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.Lire moins >
Lire la suite >Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls ( P = 0.001); half were previously unknown (AF < 0.000002). MYO6 , MYO7A , PTPRQ , and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1 N321I/+ mice, carrying the TMC1 :p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
Université de Lille
Inserm
CHU Lille
Inserm
CHU Lille
Collections :
Date de dépôt :
2022-12-08T01:34:47Z
2023-02-17T12:12:54Z
2023-02-17T12:12:54Z