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 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.

Keywords: Auditory neuropathy; Mohr-Tranebjaerg syndrome (MTS); TIMM8A.

Fig. 1

Pedigree and audiological phenotype of Family 1. a Pedigree of Family 1. The affected subject is coloured black, the proband is indicated by an arrow, and unaffected members with black spots indicate obligate carriers of the causative variation. b Audiograms of the proband (III:2) and his mother (II:4). c Normal DPOAE result of the proband. d Absence of ABR waves and present CM waves in the proband. L, Left, blue; R, Right, red

Fig. 2

Pedigree, audiological phenotype and gene variation of Family 2. a Pedigree of Family 2. The affected subject is coloured black, and the proband is indicated by an arrow. b Audiograms of the proband (III:6). c Normal DPOAE result of the proband. d Sequencing chromatograms of TIMM8A showing the deletion in affected individuals (lower panel) compared with normal controls (upper panel). L, left, blue; R, right, red

Fig. 3

Pedigree and audiological phenotype of Family 3. a Pedigree of Family 3. The affected subject is coloured black, the proband is indicated by an arrow, unaffected members with black spots indicate obligate carriers of the causative variation, and a rhombus with a question mark is a subject with unknown gender. b Audiograms of the proband (III:5) and his mother (II:5). c Speech recognition score (SRS) of the proband upon different stimulations, showing different tendency from normal controls. d Normal DPOAE result of the proband. e Absence of ABR waves and present CM waves in the proband. f Electrocochleography (ECochG) showed abnormal -SP/AP > 0.4. L, left, blue; R, right, red

Fig. 4

Gene identification in TIMM8A of Family 1. a General structure of TIMM8A protein showing the positions of variations identified in MTS patients. Red colour presents missense variation, yellow indicates nonsense variation, and green indicates frameshift. b Wild-type and mutated amino acid sequences indicating the amino acid changes after variation p.L78Sfs21, and protein alignment showing conservation from amino acids position 78 to 97 across five species. c Sequencing chromatograms of TIMM8a showing the insertion in affected individuals (lower panel) compared with that of normal controls (upper panel). The inserted nucleotides are marked by red frames. d Three-dimensional structure of TIMM8A wild-type created by SWISS-MODEL. Mutated amino acids are coloured in yellow

Fig. 5

Copy number variation including TIMM8A of Family 3. a NGS result showing the deletion in the TIMM8A gene. b Molecular cell karyotype of Xq22.1(100,593,213-100,609,547) × 0 of the proband from Family 3