Case Report: Novel Heterozygous DFNA5 Splicing Variant Responsible for Autosomal Dominant Non-syndromic Hearing Loss in a Chinese Family

Chen, Xi; Jia, Bao-Long; Li, Mei-Hui; Lyu, Yuan; Liu, Caixia

doi:10.3389/fgene.2020.569284

Cited by 4 publications

(4 citation statements)

References 21 publications

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“…For the mitochondrial genome, mt12SrRNA pathogenic genetic variants is the common cause with 142 reported patients Variants in PAX3 8 , DSPP, MYH14, GRHL2 234 and ESRRB 235 have been reported in only one case for each gene. While variants in CHD7 , 9 ILDR1 , 62 GREB1L , 63 CABP2 , 64 GSDME , 65 SLC26A5a , 66 CIB2 , 78 PEX6 , 95 SLC12A2 , 101,102 EPS8 , 155 GRXCR1 , 170 HARS2 , 175 TBC1D24 , 179 MIR96 , 209 tRNALeu , 210 SYNE4 , 236 and GPSM2 237 have been associated in three or less than three case for each gene. Most of such rare causative variants have been reported in a single family only.…”

Section: Resultsmentioning

confidence: 99%

A systematic review of the monogenic causes of Non‐Syndromic Hearing Loss (NSHL) and discussion of Current Diagnosis and Treatment options

et al. 2022

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Hearing impairment is one of the most widespread inheritable sensory disorder affecting at least 1 in every 1000 born. About two‐third of hereditary hearing loss (HHL) disorders are non‐syndromic. To provide comprehensive update of monogenic causes of non‐syndromic hearing loss (NSHL), literature search has been carried out with appropriate keywords in the following databases–PubMed, Google Scholar, Cochrane library, and Science Direct. Out of 2214 papers, 271 papers were shortlisted after applying inclusion and exclusion criterion. Data extracted from selected papers include information about gene name, identified pathogenic variants, ethnicity of the patient, age of onset, gender, title, authors' name, and year of publication. Overall, pathogenic variants in 98 different genes have been associated with NSHL. These genes have important role to play during early embryonic development in ear structure formation and hearing development. Here, we also review briefly the recent information about diagnosis and treatment approaches. Understanding pathogenic genetic variants are helpful in the management of affected and may offer targeted therapies in future.

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Section: Resultsmentioning

confidence: 99%

A systematic review of the monogenic causes of Non‐Syndromic Hearing Loss (NSHL) and discussion of Current Diagnosis and Treatment options

et al. 2022

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“…To date, more than a dozen DFNA5 families have been reported worldwide (Table 2). Although the pathogenic variants in GSDME of these families were different, these variants all caused the skipping of GSDME exon 8, led to a frameshift that changes amino acid residues 331 to 371, produced a premature stop codon at position 372 and resulted in the loss of 125 wildtype amino acids, formed a truncated protein and lost the normal carboxyl-terminal fragment [8]. This study, we aimed to report a novel c.1183 + 1 G > C splice site variant in the GSDME gene.…”

Section: Introductionmentioning

confidence: 95%

A novel splice site variant c.1183 + 1 G > C in DFNA5 causing autosomal dominant nonsyndromic hearing loss in a Chinese family

Wang²,

Liang³

et al. 2022

BMC Med Genomics

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Background The most frequent clinical presentation of autosomal dominant nonsyndromic hearing loss (ADNSHL) is bilateral, symmetrical, postlingual progressive sensorineural hearing loss, which begins with impairment at high frequencies and eventually progresses to hearing loss at all frequencies. Autosomal dominant deafness-5 (DFNA5) is a subtype of ADNSHL caused by heterozygous variants in the gasdermin E (GSDME, also known as DFNA5) gene. Methods Deafness gene NGS panel analysis were performed on the proband of a six-generation Chinese family with hearing loss. The co-segregation analysis between the hearing loss and the novel variant was analyzed by Sanger sequencing and pure-tone audiometry. The minigene splicing assay was performed to evaluate the potential effect of the variant on messenger RNA splicing in vitro. Results The family exhibited autosomal dominant, progressive, postlingual, nonsyndromic sensorineural hearing loss, which was similar to that of the previously reported DFNA5 families. A novel heterozygous splice site variant in GSDME gene intron 8 was identified, which co-segregated with the hearing loss phenotype of the family. The variant caused skipping of exon 8 in the mutant transcript, leading to the direct linking of exons 7 and 9. Conclusions We identified a novel GSDME splice site variant c.1183 + 1 G > C in an extended Chinese family, which led to the skipping of exon 8. The results extended the pathogenic variants spectrum of the GSDME gene, provided further support for the 'gain-of-function' mechanism of DFNA5, and afforded a molecular interpretation for these patients with ADNSHL.

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“…Every pathogenic GSDME mutation identified thus far has been found to cause exon 8 skipping. These variants include disruptions in the consensus splice acceptor site (Bischoff et al, 2004;Chai et al, 2014;Wang et al, 2018;Chen et al, 2020;Yuan et al, 2020;Mansard et al, 2022), the splice donor site (Cheng et al, 2007;Li-Yang et al, 2015), the intronic splicing regulatory elements (Van Laer et al, 1998;Yu et al, 2003;Park et al, 2010;Nishio et al, 2014;Nadol et al, 2015;Booth et al, 2018b;Booth et al, 2020), or exonic splicing regulatory elements (Booth et al, 2018b).…”

Section: Dfna5: a Gain-of-function Splice Alterationmentioning

confidence: 99%

Alternative splicing in shaping the molecular landscape of the cochlea

Kim

Koo²,

Bok³

2023

Front. Cell Dev. Biol.

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The cochlea is a complex organ comprising diverse cell types with highly specialized morphology and function. Until now, the molecular underpinnings of its specializations have mostly been studied from a transcriptional perspective, but accumulating evidence points to post-transcriptional regulation as a major source of molecular diversity. Alternative splicing is one of the most prevalent and well-characterized post-transcriptional regulatory mechanisms. Many molecules important for hearing, such as cadherin 23 or harmonin, undergo alternative splicing to produce functionally distinct isoforms. Some isoforms are expressed specifically in the cochlea, while some show differential expression across the various cochlear cell types and anatomical regions. Clinical phenotypes that arise from mutations affecting specific splice variants testify to the functional relevance of these isoforms. All these clues point to an essential role for alternative splicing in shaping the unique molecular landscape of the cochlea. Although the regulatory mechanisms controlling alternative splicing in the cochlea are poorly characterized, there are animal models with defective splicing regulators that demonstrate the importance of RNA-binding proteins in maintaining cochlear function and cell survival. Recent technological breakthroughs offer exciting prospects for overcoming some of the long-standing hurdles that have complicated the analysis of alternative splicing in the cochlea. Efforts toward this end will help clarify how the remarkable diversity of the cochlear transcriptome is both established and maintained.

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Case Report: Novel Heterozygous DFNA5 Splicing Variant Responsible for Autosomal Dominant Non-syndromic Hearing Loss in a Chinese Family

Cited by 4 publications

References 21 publications

A systematic review of the monogenic causes of Non‐Syndromic Hearing Loss (NSHL) and discussion of Current Diagnosis and Treatment options

A systematic review of the monogenic causes of Non‐Syndromic Hearing Loss (NSHL) and discussion of Current Diagnosis and Treatment options

A novel splice site variant c.1183 + 1 G > C in DFNA5 causing autosomal dominant nonsyndromic hearing loss in a Chinese family

Alternative splicing in shaping the molecular landscape of the cochlea

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