Novel Compound Heterozygous Mutations in MYO7A Associated with Usher Syndrome 1 in a Chinese Family

Gao, Xue; Wang, Guojian; Yuan, Yongyi; Xin, Feng; Han, Mingyu; Lu, Jingqiao; Zhao, Hui; Yu, Fei; Xu, Jin; Jiang, Dong; Lin, Xiaobo; Dai, Pu

doi:10.1371/journal.pone.0103415

Cited by 7 publications

(7 citation statements)

References 29 publications

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“…The details of the deafness gene capture, sequencing, and bioinformatics analysis methods have been described in detail previously [ 7 ]. According to the autosomal recessive pattern of inheritance, only variants that were homozygous or compound heterozygous in the affected siblings were selected as candidates.…”

Section: Methodsmentioning

confidence: 99%

Novel Mutations and Mutation Combinations ofTMPRSS3Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment

Gao

Yuan

Wang

et al. 2017

BioMed Research International

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Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in the TMPRSS3 gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8). TMPRSS3 mutations can be classified as mild or severe, and the phenotype is dependent on the combination of TMPRSS3 mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milder TMPRSS3 mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations in TMPRSS3, one novel mutation c.36delC [p.(Phe13Serfs⁎12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfs⁎12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfs⁎12). We concluded that different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family.

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Section: Methodsmentioning

confidence: 99%

Novel Mutations and Mutation Combinations ofTMPRSS3Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment

Gao

Yuan

Wang

et al. 2017

BioMed Research International

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“…Fortunately, molecular diagnosis through next-generation sequencing (NGS) has made it easier to diagnose deafness syndromes such as MTS, making diagnosis possible decades earlier, before all the phenotypes show. 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].…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Yang

et al. 2019

BMC Med Genet

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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.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0741-3) contains supplementary material, which is available to authorized users.

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“…Although the clinical data to date indicate the NSHL phenotype in this family, the diagnosis of Usher syndrome cannot be totally excluded since MYO7A ‐related Usher syndrome usually presents with late‐onset retinal pigmented epithelium. The clinical features of Usher syndrome vary among and between families, especially with respect to the age of onset of eye disorder 30,39 . Further, one report suggested that DFNB2 and Usher syndrome patients may share the same mutations in MYO7A ‐mutated families 39 .…”

Section: Discussionmentioning

confidence: 99%

Novel compound heterozygous synonymous and missense variants in the MYO7A gene identified by next‐generation sequencing in a Chinese family with nonsyndromic hearing loss

Xiang

et al. 2022

Clinical Laboratory Analysis

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Background Variants in the MYO7A gene are increasingly identified among patients suffering from Usher syndrome type 1B (USH1B). However, such mutations are less commonly detected among patients suffering from nonsyndromic hearing loss (NSHL), including autosomal recessive deafness (DFNB2) and autosomal dominant deafness (DFNA11). This research attempts to clarify the genetic base of DFNB2 in a Chinese family and determine the pathogenicity of the identified mutations. Method Targeted next‐generation sequencing (TGS) of 127 known deafness genes was performed for the 14‐year‐old proband. Then, Sanger sequencing was performed on the available family members. A minigene splicing assay was performed to verify the impact of the novel MYO7A synonymous variant. After performing targeted next‐generation sequencing (TGS) of 127 existing hearing loss‐related genes in a 14‐year‐old proband, Sanger sequencing was carried out on the available family members. Then, to confirm the influence of the novel MYO7A synonymous variants, a minigene splicing assay was performed. Results Two heteroallelic mutants of MYO7A (NM_000260.3) were identified: a maternally inherited synonymous variant c.2904G > A (p.Glu968=) in exon 23 and a paternally inherited missense variant c.5994G > T (p.Trp1998Cys) in exon 44. The in vitro minigene expression indicated that c.2904G > A may result in skipping of exon 23 resulting in a truncated protein. Conclusions We reported a novel missense (c.5994G > T) and identified, for the first time, a novel pathogenic synonymous (c.2904G > A) variant within MYO7A in a patient with DFNB2. These findings enrich our understanding of the MYO7A variant spectrum of DFNB2 and can contribute to accurate genetic counseling and diagnosis of NSHL patients.

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Novel Compound Heterozygous Mutations in MYO7A Associated with Usher Syndrome 1 in a Chinese Family

Cited by 7 publications

References 29 publications

Novel Mutations and Mutation Combinations ofTMPRSS3Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment

Novel Mutations and Mutation Combinations ofTMPRSS3Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment

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

Novel compound heterozygous synonymous and missense variants in the MYO7A gene identified by next‐generation sequencing in a Chinese family with nonsyndromic hearing loss

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