title: Mitochondrial mutations associated with aminoglycoside ototoxicity and hearing loss susceptibility identified by meta-analysis.
abstract: BACKGROUND
  Genetic variations, including mitochondrial mutations, are important contributors to hearing loss, especially in children, and newborn genetic screens for hearing loss mutations are becoming increasingly common. Mitochondrial mutations have been linked with ototoxic responses to common antibiotics, therefore understanding the association of these mutations with hearing loss is of special importance. To address the usefulness of screening for these mutations in a clinical setting, we formed a collaboration of clinicians and geneticists to analyse the association of mitochondrial mutations with non-syndromic hearing loss, including the effect of ethnicity, audiological test methods and aminoglycoside exposure.
  
  
  METHODS
  This survey identified 122 variants in 43 studies that have been assessed for an association with hearing loss, and meta-analysis was performed on clinically relevant subsets. RNA folding and conservation analysis further explored possible relevance of these variants.
  
  
  RESULTS
  Among all studies, eight variants were found to have significant associations with hearing loss. A partially overlapping set of six variants had significant association with hearing loss when aminoglycoside exposure was assessed. Five of these variants predictive of sensitivity to aminoglycoside spatially co-localise in an RNA folding model. There was little effect of the audiological test method used to assess hearing loss on the association with the variants.
  
  
  CONCLUSIONS
  Our results found a small set of studied variants had reproducible association with hearing loss, which will help clarify mutations useful in genetic screens for hearing loss. Several of the aminoglycoside exposure-associated mutations may co-localise on folded 12S rRNA, suggesting a functional association between these loci and aminoglycoside-induced hearing loss.
authors.affiliation: Institute of Genomic and Personalized Medicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Jing
authors.affiliation: Institute of Genomic and Personalized Medicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zongjie
authors.affiliation: Institute of Genomic and Personalized Medicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Fu
authors.initials: F
authors.lastname: Denggang
authors.affiliation: Institute of Genomic and Personalized Medicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Hei
authors.initials: H
authors.lastname: Na
authors.affiliation: Wuhan Women and Children Hospital, Wuhan, Hubei, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Bin
authors.affiliation: Wuhan Women and Children Hospital, Wuhan, Hubei, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Aifen
authors.affiliation: Wuhan Women and Children Hospital, Wuhan, Hubei, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Xijiang
authors.affiliation: Wuhan Women and Children Hospital, Wuhan, Hubei, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Cong
authors.affiliation: Wuhan Bureau of Health, Wuhan, Hubei, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yunping
authors.affiliation: Institute of Genomic and Personalized Medicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Huijun Z
authors.initials: HZ
authors.lastname: Ring
authors.affiliation: Institute of Genomic and Personalized Medicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Brian Z
authors.initials: BZ
authors.lastname: Ring
mesh_terms: D000617:Aminoglycosides / Q000009:adverse effects*; D001299:Audiometry; D001483:Base Sequence; D004272:DNA, Mitochondrial / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D020022:Genetic Predisposition to Disease; D034381:Hearing Loss / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009690:Nucleic Acid Conformation; D012335:RNA, Ribosomal / Q000737:chemistry / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S
keywords: Clinical genetics; Genetic screening/counselling