@misc{10481/106621,
year = {2025},
month = {9},
url = {https://hdl.handle.net/10481/106621},
abstract = {Meniere disease (MD) is a chronic inner ear disorder with significant heritability. This study compares the burden of rare highand moderate-impact coding variants in an MD cohort to determine whether genetic burden in sporadic MD (SMD) overlaps
familial MD (FMD), potentially revealing hidden inheritance in SMD. Exome sequencing identified rare variants in unrelated
FMD (N = 93) and SMD (N = 287) patients. Gene Burden Analysis (GBA) was performed, and candidate genes were prioritized
using the number of variant carriers, inner-ear expression, and hearing/balance-related phenotypic annotations. FMD patients
showed higher accumulation of missense and loss-of-function variants than SMD, especially in genes linked to auditory and
vestibular function. GBA identified 269 enriched genes in SMD, with 31 annotated for inner ear phenotypes, while FMD had 432
with 51 pinpointed. Sporadic and FMD overlapped in 28.1% of enriched genes, with ADGRV1, MEGF8, and MYO7A most commonly
shared. Auditory brainstem responses from knockout mouse models supported hearing loss of three novel MD candidate genes
(NIN, CCDC88C, and ANKRD24), consistent with patient hearing profiles. In conclusion, SMD and FMD have a divergent genetic
architecture. The enrichment of missense variants in stria vascularis and hair cell stereocilia genes supports distinct pathogenic
mechanisms and a multiallelic-recessive inheritance pattern in MD.},
organization = {Andalusian University, Research and Innovation Department. Grant Number: PREDOC2021/00343},
organization = {University of Sydney. Grant Number: K7013_B341},
organization = {Andalusian Health Department. Grant Numbers: PI-0266-2021 GEN4PHEN, PI027-2020},
organization = {Asociación Síndrome de Meniere España - Meniere's Society, UK},
organization = {Instituto de Salud Carlos III. Grant Number: PI22/01838},
publisher = {John Wiley & Sons Australia, Ltd},
keywords = {Exome sequencing},
keywords = {Genetic diagnosis},
keywords = {Genomics},
title = {Different Contribution of Missense and Loss-of-Function Variants to the Genetic Structure of Familial and Sporadic Meniere Disease},
doi = {10.1002/mco2.70394},
author = {Parra Pérez, Alberto Manuel and Gallego Martinez, Álvaro and Escalera Balsera, Alba and Robles Bolívar, Paula and Pérez Carpena, Patricia and Lopez-Escamez, Jose A.},
}