@misc{10481/91984,
year = {2024},
month = {3},
url = {https://hdl.handle.net/10481/91984},
abstract = {Meniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial
MD (FMD) has been reported, being 9–10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in
FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance.
We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population.
Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different
populations. For this purpose, the coding regions with high constraint (low density of rare variants) were retrieved in the
OTOG coding sequence in Non-Finnish European (NFE).. Missense variants (AF < 0.01) were selected from a 100 FMD
patient cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds
ratios were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in
13 FMD patients, with 2 variants (rs61978648 and rs61736002) shared by 5 individuals and another variant (rs117315845)
shared by two individuals. The results confirm the observed enrichment of OTOG rare missense variants in FMD. Furthermore,
eight variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling
predicts five missense variants that could alter the otogelin stability. We conclude that several variants reported in FMD
are in constraint regions, and they may have a founder effect and explain the burden of FMD in the European population.},
organization = {Open Access funding enabled and organized by CAUL and its
Member Institutions},
organization = {Biomedicine Program at Universidad de Granada, supported by Andalusian University, Research and Innovation Department
(Grant# PREDOC2021/00343)},
organization = {Andalusian University, Research and Innovation
Department (Grant DOC_01677)},
organization = {Andalusian Health Department
(Grant PI-0266-2021 GEN4PHEN)},
organization = {Cures Within
Reach and the Knight family},
organization = {The University of
Sydney (K7013_B3413 Grant)},
organization = {Instituto de Salud Carlos III (Grant#
PI20-1126)},
organization = {CIBERER (Grant# PIT21_GCV21)},
organization = {Andalusian University,
Research and Innovation Department (2020 B-CTS-68-UGR20,
M3NOMIC; PY20-00303, EPIMEN)},
organization = {Andalusian Health Department
(Grant# PI027-2020)},
organization = {Asociación Sindrome de Meniere España
(ASMES)},
organization = {Meniere’s Society, UK},
publisher = {Springer Nature},
keywords = {Meniere’s disease},
keywords = {Hearing loss},
keywords = {Exome sequencing},
title = {An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population},
doi = {10.1007/s00439-024-02643-8},
author = {Parra Pérez, Alberto M. and Gallego Martínez, Álvaro and López Escámez, José Antonio},
}