Abstract
Objectives Meniere’s disease (MD) is a rare inner ear disorder characterized by sensorineural hearing loss, episodic vertigo and tinnitus. Familial MD has been reported in 6-9% of sporadic cases, and few genes including FAM136A, DTNA, PRKCB, SEMA3D and DPT have been involved in single families, suggesting genetic heterogeneity. In this study, the authors recruited 46 families with MD to search for relevant candidate genes for hearing loss in familial MD.
Design Exome sequencing data from MD patients were analyzed to search for rare variants in hearing loss genes in a case-control study. A total of 109 patients with MD (73 familial cases and 36 early-onset sporadic patients) diagnosed according to the diagnostic criteria defined by the Barany Society were recruited in 11 hospitals. The allelic frequencies of rare variants in hearing loss genes were calculated in individuals with familial MD. A single rare variant analysis (SRVA) and a gene burden analysis (GBA) were conducted in the dataset selecting one patient from each family. Allelic frequencies from European and Spanish reference datasets were used as controls.
Results A total of 5136 single nucleotide variants in hearing loss genes were considered for SRVA in familial MD cases, but only one heterozygous variant in the OTOG gene (rs552304627) was found in two unrelated families. The GBA found an enrichment of rare missense variants in the OTOG gene in familial MD. So, 15/46 families (33%) showed at least one rare missense variant in the OTOG gene, suggesting a key role in familial MD.
Conclusions The authors found an enrichment of multiplex rare missense variants in the OTOG gene in familial MD. This finding supports OTOG as a relevant gene in familial MD and set the groundwork for genetic testing in MD.
Footnotes
Conflicts of Interest and Source of Funding: Jose Antonio Lopez Escamez (JALE) is partially funded by INT18/00031 from ISCIII. This study was funded by the Luxembourg National Research Fund
INTER/Mobility/17/11772209 Grant and EF-0247-2017 from Andalusian Health Government to JALE. Authors declare no conflict of interest.