Pablo Roman-Naranjo1, Alvaro Gallego-Martinez1, Andrés Soto-Varela2, Ismael Aran3, Maria Del Carmen Moleon4, Juan Manuel Espinosa-Sanchez4, Juan Carlos Amor-Dorado5, Angel Batuecas-Caletrio6, Paz Perez-Vazquez7, Jose Antonio Lopez-Escamez1,4,8. 1. Otology & Neurotology Group CTS 495, Department of Genomic Medicine, Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica, Granada, Spain. 2. Division of Otoneurology, Department of Otorhinolaryngology, Complexo Hospitalario Universitario, Santiago de Compostela, Spain. 3. Department of Otolaryngology, Complexo Hospitalario de Pontevedra, Pontevedra, Spain. 4. Department of Otolaryngology, Instituto de Investigación Biosanitaria, ibs.GRANADA, Hospital Universitario Virgen de las Nieves, Granada, Spain. 5. Department of Otolaryngology, Hospital Can Misses, Ibiza, Spain. 6. Department of Otolaryngology, Hospital Universitario Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain. 7. Department of Otorhinolaryngology, Hospital Universitario de Cabueñes, Gijón, Spain. 8. Department of Surgery, Division of Otolaryngology, Universidad de Granada, Granada, Spain.
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 to 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 and a gene burden analysis (GBA) were conducted in the dataset selecting 1 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 single rare variant analysis in familial MD cases, but only 1 heterozygous likely pathogenic variant in the OTOG gene (rs552304627) was found in 2 unrelated families. The gene burden analysis found an enrichment of rare missense variants in the OTOG gene in familial MD. So, 15 of 46 families (33%) showed at least 1 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.
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 to 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 and a gene burden analysis (GBA) were conducted in the dataset selecting 1 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 single rare variant analysis in familial MD cases, but only 1 heterozygous likely pathogenic variant in the OTOG gene (rs552304627) was found in 2 unrelated families. The gene burden analysis found an enrichment of rare missense variants in the OTOG gene in familial MD. So, 15 of 46 families (33%) showed at least 1 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.
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Authors: Pablo Roman-Naranjo; Alberto M Parra-Perez; Alba Escalera-Balsera; Andres Soto-Varela; Alvaro Gallego-Martinez; Ismael Aran; Nicolas Perez-Fernandez; David Bächinger; Andreas H Eckhard; Rocio Gonzalez-Aguado; Lidia Frejo; Jose A Lopez-Escamez Journal: Clin Transl Med Date: 2022-06
Authors: Shoujun Gu; Rafal Olszewski; Ian Taukulis; Zheng Wei; Daniel Martin; Robert J Morell; Michael Hoa Journal: Sci Rep Date: 2020-10-22 Impact factor: 4.996