Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy

作者：Hongyang Wang, Li Wang, Ju Dong Yang, Linwei Yin, Lan Lan, Jin Li, Qiujing Zhang, Dayong Wang, Jing Guan, Qiuju Wang · 发表于：BMC Medical Genetics · 年份：2019 · DOI：10.1186/s12881-018-0741-3 · 被引用次数：25 · 研究领域：Mitochondrial Function and Pathology、Hearing, Cochlea, Tinnitus, Genetics、Neuroscience of respiration and sleep

BACKGROUND: Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder resulting in early-onset hearing impairment, gradual dystonia and optic atrophy. MTS is caused by variations in the nuclear TIMM8A gene, which is involved in mitochondrial transport of metabolites. This study aimed to identify the pathogenic gene variations in three Chinese families associated with predicted MTS with or without X-linked agammaglobulinaemia. METHODS: Otologic examinations, vestibular, neurological, optical and other clinical evaluations were conducted on the family members. Targeted genes capture combining next generation sequencing (NGS) was performed, and then Sanger sequencing was used to confirm the causative variation. RESULTS: A novel variation, c.232_233insCAAT, in TIMM8A was identified as the pathogenic variation in one Chinese family. This variation co-segregated with the most frequent phenotypic deafness and was absent in the 1000 Genomes Project, ExAC and 1751 ethnicity-matched controls. Clinically, otological examinations illustrated the typical postsynaptic auditory neuropathy for the proband without the symptoms of dystonia or optic atrophy. MRI demonstrated abnormal small cochlear symmetric nerves, while the vestibular function appeared to be less influenced. Furthermore, we found another two TIMM8A variations, the deletion c.133_135delGAG and a copy number variation (CNV) including the TIMM8A gene, in two independent case, when we performed NGS o...