Abstract
BackgroundMohr-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.MethodsOtologic 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.ResultsA 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 on an auditory neuropathy population.ConclusionWe identified two novel variations in the TIMM8A gene (c.232_233insCAAT and c.133_135delGAG) and a CNV including the TIMM8A gene in three independent Chinese families with predicted MTS. To our knowledge, this is the first report of TIMM8A variations being identified in a Chinese population. Our results enrich the variation spectrum of TIMM8A and clinical heterogeneity of MTS. Genetic detection and diagnosis is a powerful tool for better understanding and managing syndromic hearing impairments, such as MTS, before they become full-blown.
Highlights
Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder resulting in early-onset hearing impairment, gradual dystonia and optic atrophy
We identified a novel frameshift variation in the TIMM8A gene in this Chinese family with auditory neuropathy, who visited the outpatient department for deafness genetic consultation, as typical auditory neuropathy was the only phenotype in the proband at this stage
Clinical evaluations Three probands, from Family 1, Family 2 and Family 3, who were diagnosed with auditory neuropathy and their parents were recruited (Fig. 1a, Fig. 2a and Fig. 3a), written informed consents were obtained from the of kin on the behalf of the minors/children participants involved in this study
Summary
Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder resulting in early-onset hearing impairment, gradual dystonia and optic atrophy. This study aimed to identify the pathogenic gene variations in three Chinese families associated with predicted MTS with or without X-linked agammaglobulinaemia. Mohr-Tranebjaerg syndrome, known as deafness-dystonia-optic neuronopathy (MTS/DDON, MIM304700) syndrome, is a rare X-linked recessive neurodegenerative disease. It is characterized by early-onset progressive auditory neuropathy followed by dystonia and optic atrophy in adolescence or adulthood. Targeted deafness genes combined with high-throughput sequencing can be regarded as a revolutionary technology with high speed and low cost to identify the pathogenic causes in a large number of syndromic hearing loss families [8, 9]
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