Targeted gene capture and massively parallel sequencing identify <i>TMC1</i> as the causative gene in a six‐generation Chinese family with autosomal dominant hearing loss

Gao, Xue; Huang, Shasha; Yuan, Yongyi; Wang, Guojian; Xu, Jin; Yu-bin, JI; Han, Mingyu; Yu, Fei; Kang, Dongyang; Lin, Xiaobo; Dai, Pu

doi:10.1002/ajmg.a.37206

Cited by 13 publications

(9 citation statements)

References 54 publications

(63 reference statements)

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“…For the four TMC1 dominant variants, c.1714G>A (p.D572N) and c.1714G>C (p.D572H) affect the same nucleotide, which is proposed to be a recurrent site of variants. The c.1714G>A detected in Family 02 is a known and common dominant variant, accounting for approximately 4.4% (3/68) of ADNSHL in the Chinese population (Gao et al., ). The c.1714G>A variant is located within a cytoplasmic loop between TM4 and TM5 that may play a critical role in forming the pore subunit of the transduction channel (Gao et al., ; Hilgert et al., ; Kurima et al., ; Labay, Weichert, Makishima, & Griffith, ).…”

Section: Discussionmentioning

confidence: 99%

“…The c.1714G>A detected in Family 02 is a known and common dominant variant, accounting for approximately 4.4% (3/68) of ADNSHL in the Chinese population (Gao et al., ). The c.1714G>A variant is located within a cytoplasmic loop between TM4 and TM5 that may play a critical role in forming the pore subunit of the transduction channel (Gao et al., ; Hilgert et al., ; Kurima et al., ; Labay, Weichert, Makishima, & Griffith, ). The c.1253T>A variant identified in Family 01 is another well‐known dominant TMC1 variant, which has been reported by our group previously; this is the second report of this variant worldwide.…”

Section: Discussionmentioning

confidence: 99%

“…The former appears primarily as congenital or prelingual severe/profound hearing impairment, while the latter shows postlingual progressively aggravated hearing loss. To date, 59 different types of DFNB7/11 variants and four DFNA36 variants have been identified in hereditary hearing loss families (Figure and Appendix ; Bademci et al., ; Bakhchane et al., ; Brownstein et al., ; Chen et al., ; Davoudi‐Dehaghani, Fallah, Tavakkoly‐Bazzaz, Bagherian, & Zeinali, ; de Heer et al., ; Ganapathy et al., ; Gao et al., , ; Hilgert et al., ; Hu et al., ; Imtiaz et al., ; Kalay et al., ; Kitajiri, Makishima, Friedman, & Griffith, ; Kitajiri, McNamara, et al., ; Kurima et al., ; Lin et al., ; Meyer et al., ; Riahi et al., ; Santos et al., ; Schrauwen et al., ; Shafique et al., ; Sirmaci et al., ; Tlili et al., ; Yang et al., ; Yang, Wei, Chai, Li, & Wu, ; Zhao et al., ). With the rapid development in sequencing technology, such as high‐throughput sequencing (HTS), which has the advantages of low sample quantity, low cost, and high efficiency, more TMC1 variants have been reported in various regions, such as Ecuador, Algerian, Morocco, and China.…”

Section: Introductionmentioning

confidence: 99%

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Identification of four TMC1 variations in different Chinese families with hereditary hearing loss

Wang

Guan

et al. 2018

Molec Gen & Gen Med

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BackgroundVariants in TMC1 (transmembrane channel‐like 1) can cause both autosomal dominant and recessive hearing loss in human population. Mice with Tmc1 variants have been shown to be ideal animal models for gene therapy. In this article, we report four TMC1 variants in four different Chinese families and the follow‐up auditory phenotype of a previously reported family.MethodsFour families with TMC1 variants, as well as a previously described family with TMC1 variant orthologous to the Beethoven mouse, were recruited in this study. A comprehensive auditory evaluation was performed on all ascertained family members. High‐throughput sequencing was conducted using genomic DNA from the probands and other family members to identify probable deafness genes.ResultsWe identified four TMC1 (NM_138691.2) variations, including two pathogenic variants, c.1714G>A, and c.1253T>A, one likely pathogenic variant, c.[797T>C];[797T>C], and one single nucleotide polymorphism (SNP), c.2276G>A. Among these variants, c.[797T>C];[797T>C] is a novel likely pathogenic variant, and c.1714G>A and c.1253T>A are known pathogenic variants at the DFNB7/11 (DFNA36) locus. Phenotype‐genotype correlation analysis of TMC1 variants showed that the TMC1 dominant variation‐related phenotype was late‐onset, progressive, high frequency to all frequency sensorineural hearing loss, while the TMC1 recessive variant was related to congenital all frequency sensorineural hearing impairment.ConclusionsTwo pathogenic, one likely pathogenic variants and one SNP of TMC1 were identified in four Chinese families with hereditary hearing loss, indicating that TMC1 may be a more frequent cause of hearing loss than expected. TMC1 variants related to hearing loss result in specific phenotypes. The TMC1 c.1253T>A (p.M418K) variation, homologous to the Tmc1 c. 1235 T> A (p.M412K) variant in Beethoven mice, was the second report of this variant in human patients with hearing loss, suggesting the possibility to translational gene therapy from Beethoven mice to human patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of four TMC1 variations in different Chinese families with hereditary hearing loss

Wang

Guan

et al. 2018

Molec Gen & Gen Med

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“…In deafness pedigrees, variants affecting protein function in 12 genes were verified with the positive diagnostic rate 56.67% (17/30) ( Table 3). Detailed information on these deafness pedigrees is provided in our previous studies [22][23][24][25][26][27][28][29].…”

Section: Positive Diagnostic Rate For Snvsmentioning

confidence: 99%

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Yuan

et al. 2019

Eur J Hum Genet

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Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.

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“…In China, recent studies on TMC1 mutations such as c.589G>A, c.1171C>T (Xue et al, 2013), c.1209G>C (Tao et al, 2013Tao, Xiaoming, Yongchuan, Lei, & Hao, 2013), c.1253T>A (Yali et al, 2014), c.1714G>A (Xue et al, 2015), and c.1979C>T (Jiongjiong et al, 2016) have been reported. All mutations were analyzed by genetic testing of sporadic families without regional specificity.…”

Section: Discussionmentioning

confidence: 99%

Mutation spectra and founder effect of TMC1 in patients with non‐syndromic deafness in Xiamen area, China

Jiang

Gao

et al. 2017

American J of Med Genetics Pt B

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To analyze the spectrum and founder effect of TMC1 mutations in patients with non‐syndromic deafness in the Xiamen area. Sporadic pedigrees were detected by targeted next‐generation sequencing, and 110 unrelated patients from Xiamen Special Education School were analyzed through Sanger sequencing for the TMC1 gene. In total, 53 SNPs were designed to analyze the haplotypes of the TMC1 c.2050G>C mutation. The probands of three families were found to be homozygous for TMC1 c.2050G>C, and their parents were all heterozygous for the TMC1 c.2050G>C mutation. In 110 unrelated patients from Xiamen Special Education School, four were found to carry compound heterozygotes of TMC1 c.2050G>C, which were compound heterozygotes of c.804G>A, c.1127T>C, c.1165C>T, and c.1396_1398delAAC, respectively. Three types of TMC1 polymorphisms (c.45C>T, c.1713C>T, c.2208+49C>T) and two heterozygotes of novel variants (c.1764‐4C>A, c.2073G>A[p.K691K]) were found in the remaining 100 patients. In total, four novel variants were detected in this study. These mutations and variants were not detected in 100 normal samples. The haplotypes of the probands of families with TMC1 c.2050G>C were identical. There were unique hotspots and spectra of TMC1 mutations in the Xiamen deaf population. Haplotype analysis is useful to understand the founder effect of the hot spot mutation.

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Targeted gene capture and massively parallel sequencing identify TMC1 as the causative gene in a six‐generation Chinese family with autosomal dominant hearing loss

Cited by 13 publications

References 54 publications

Identification of four TMC1 variations in different Chinese families with hereditary hearing loss

Identification of four TMC1 variations in different Chinese families with hereditary hearing loss

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Mutation spectra and founder effect of TMC1 in patients with non‐syndromic deafness in Xiamen area, China

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