Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy
Abstract 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 metabol...
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | BMC Medical Genetics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12881-018-0741-3 |
| _version_ | 1819168758450618368 |
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| author | Hongyang Wang Li Wang Ju Yang Linwei Yin Lan Lan Jin Li Qiujing Zhang Dayong Wang Jing Guan Qiuju Wang |
| author_facet | Hongyang Wang Li Wang Ju Yang Linwei Yin Lan Lan Jin Li Qiujing Zhang Dayong Wang Jing Guan Qiuju Wang |
| author_sort | Hongyang Wang |
| collection | DOAJ |
| description | Abstract 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 on an auditory neuropathy population. Conclusion We 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. |
| first_indexed | 2024-12-22T19:08:42Z |
| format | Article |
| id | doaj.art-b37380594aef475eb0753ffa9470a6b0 |
| institution | Directory Open Access Journal |
| issn | 1471-2350 |
| language | English |
| last_indexed | 2024-12-22T19:08:42Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genetics |
| spelling | doaj.art-b37380594aef475eb0753ffa9470a6b02022-12-21T18:15:44ZengBMCBMC Medical Genetics1471-23502019-01-0120111210.1186/s12881-018-0741-3Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathyHongyang Wang0Li Wang1Ju Yang2Linwei Yin3Lan Lan4Jin Li5Qiujing Zhang6Dayong Wang7Jing Guan8Qiuju Wang9Institute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLAInstitute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLAInstitute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLABGI-ShenzhenInstitute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLAInstitute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLAInstitute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLAInstitute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLAInstitute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLAInstitute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLAAbstract 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 on an auditory neuropathy population. Conclusion We 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.http://link.springer.com/article/10.1186/s12881-018-0741-3Auditory neuropathyMohr-Tranebjaerg syndrome (MTS)TIMM8A |
| spellingShingle | Hongyang Wang Li Wang Ju Yang Linwei Yin Lan Lan Jin Li Qiujing Zhang Dayong Wang Jing Guan Qiuju Wang Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy BMC Medical Genetics Auditory neuropathy Mohr-Tranebjaerg syndrome (MTS) TIMM8A |
| title | Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy |
| title_full | Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy |
| title_fullStr | Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy |
| title_full_unstemmed | Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy |
| title_short | Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy |
| title_sort | phenotype prediction of mohr tranebjaerg syndrome mts by genetic analysis and initial auditory neuropathy |
| topic | Auditory neuropathy Mohr-Tranebjaerg syndrome (MTS) TIMM8A |
| url | http://link.springer.com/article/10.1186/s12881-018-0741-3 |
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