A novel missense mutation in the C2C domain of otoferlin causes profound hearing impairment in an Omani family with auditory neuropathy

Al-Wardy, Nadia; Al-Kindi, Mohammed Nasser; Al-Khabouri, Mazin Jawad; Tamimi, Yahya; Camp, Guy Van

doi:10.15537/smj.2016.10.14967

Cited by 11 publications

(7 citation statements)

References 35 publications

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“…Among them, the G>A nucleotide change at position 4960 was located in the exon/intron junction that was expected to result in aberrant splicing, thus causing an abnormal amino acid chain of the otoferlin protein. The reported missense mutation c.1469C>G was located in the relevant C2C domain and was confirmed to affect the function of protein products [23]. The mutation c.2675A>G was found in the region between the C2C and C2D domains and was predicted to result in deleterious splicing.…”

Section: Discussionmentioning

confidence: 87%

“…Pathogenic variants in the OTOF gene identified in this study. 1469C>G) in the OTOF gene[23,24,26]. Combining the verification by the Sanger sequencing in the corresponding parents and siblings (Table3), variants c.[2688del];[2688del], c.[4960G>A];[1469C>G], and c.[2675A>G];[2977_ 2978del] were confirmed to be likely pathogenic/pathogenic for three families.…”

mentioning

confidence: 88%

“…The mutation c.1469C>G (p.Pro490Arg) was rare in the normal population database (PM2). In an Omani family with auditory neuropathy, the five affected children were all homozygous for the p.Pro490Arg mutations [23] (PM3). Computational softwares supported the pathogenicity of c.1469C>G (PP3).…”

Section: Whole-exome Sequencing Identified Candidatementioning

confidence: 99%

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Auditory Neuropathy Spectrum Disorder (ANSD)—Clinical Characteristics and Pathogenic Variant Analysis of Three Nonsyndromic Deafness Families

Zhai

Feng

et al. 2020

BioMed Research International

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Objective. To analyze the phenotypic features and pathogenic variants of three unrelated families presenting with nonsyndromic auditory neuropathy spectrum disorder (ANSD). Methods. Three recruited families that were affected by congenital deafness were clinically evaluated, including a detailed family history and audiological and radiological examination. The peripheral blood of all patients and their parents was collected for DNA extraction, and then, the exonic and flanking regions were enriched and sequenced using targeted capture and high-throughput sequencing technology. Bioinformatics analyses and the Sanger sequencing were carried out to screen and validate candidate pathogenic variants. The pathogenicity of candidate variants was evaluated by an approach that was based on the standards and guidelines for interpreting genetic variants as proposed by the American College of Medical Genetics and Genomics (ACMG). Results. Four patients in three families were diagnosed as nonsyndromic ANSD, and all exhibited OTOF gene mutations. Among them, two individuals in family 1 (i.e., fam 1-II-2 and fam 1-II-3) carried homozygous variants c.[2688del];[2688del] (NM_194248.3). Two individuals from family 2 (fam 2-II-1) and family 3 (fam 3-II-4) carried compound heterozygous variants c.[4960G>A];[1469C>G] and c.[2675A>G];[2977_2978del], respectively. Conclusions. Three unrelated pedigrees with ANSD were caused by pathogenic variants in the OTOF gene. Five mutations were found and included c.2688del, c.2675A>G, c.2977_2978del, c.4960G>A, and c.1469C>G, of which the first two are novel and expanded mutational spectrum of the OTOF gene, thus having important implications for genetic counseling of the family.

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Section: Discussionmentioning

confidence: 87%

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confidence: 88%

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Auditory Neuropathy Spectrum Disorder (ANSD)—Clinical Characteristics and Pathogenic Variant Analysis of Three Nonsyndromic Deafness Families

Zhai

Feng

et al. 2020

BioMed Research International

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“…Genetic mutation in otoferlin leads to severe hearing impairment resulting from improper HC synaptic development and lack of synaptic vesicle exocytosis. [ 95 96 ]…”

Section: O Toferlinmentioning

confidence: 99%

Cochlear proteins associated with noise-induced hearing loss: An update

Jain¹,

Pingle²,

Tumane³

et al. 2018

Indian J Occup Environ Med

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Noise-induced hearing loss (NIHL) is one of the major occupational disease that has influence on the quality of life of mining workers. Several reports suggest NIHL is attributed to noise exposure at workplace and approximately 16% of hearing loss is due to it. NIHL occurs as a result of exposure to high-level noise (>85 dB) in the workplace. Noise disrupts proteins present in the micromachinery of the ear that is required for mechano-electric transduction of sound waves. High-level noise exposure can lead to hearing impairment owing to mechanical and metabolic exhaustion in cochlea, the major organ responsible for resilience of sound. Several key proteins of cochlea include tectorial membrane, inner hair cells, outer hair cells, and stereocilia are damaged due to high-level noise exposure. Numerous studies conducted in animals have shown cochlear proteins involvement in NIHL, but the pertinent literature remains limited in humans. Detection of proteins and pathways perturbed within the micromachinery of the ear after excessive sound induction leads toward the early identification of hearing loss. The situation insisted to present this review as an update on cochlear proteins associated with NIHL after an extensive literature search using several electronic databases which help to understand the pathophysiology of NIHL.

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“…A survey conducted in 2016 indicated that up to 49% of Omani marriages were consanguineous [1]. As a result, 70% of hearing loss cases in Oman were reported as possible inherited forms and until now, two genes have been reported to be involved in nonsyndromic autosomal recessive genetic deafness in Oman, MYO15A, and Otoferlin [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

In silico analysis of a novel causative mutation in Cadherin23 gene identified in an Omani family with hearing loss

Al-Kindi

Al-Khabouri

Al-Lamki

et al. 2020

Journal of Genetic Engineering and Biotechnology

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Background: Hereditary hearing loss is a heterogeneous group of complex disorders with an overall incidence of one in every 500 newborns presented as syndromic and non-syndromic forms. Cadherin-related 23 (CDH23) is one of the listed deafness causative genes. It is found to be expressed in the stereocilia of hair cells and in the retina photoreceptor cells. Defective CDH23 have been associated mostly with prelingual severe-to-profound sensorineural hearing loss (SNHL) in either syndromic (USH1D) or non-syndromic SNHL (DFNB12) deafness. The purpose of this study was to identify causative mutations in an Omani family diagnosed with severe-profound sensorineural hearing loss by whole exome sequencing technique and analyzing the detected variant in silico for pathogenicity using several in silico mutation prediction software. Results: A novel homozygous missense variant, c.A7436C (p. D2479A), in exon 53 of CDH23 was detected in the family while the control samples were all negative for the detected variant. In silico mutation prediction analysis showed the novel substituted D2479A to be deleterious and protein destabilizing mutation at a conserved site on CDH23 protein. Conclusion:In silico mutation prediction analysis might be used as a useful molecular diagnostic tool benefiting both genetic counseling and mutation verification. The aspartic acid 2479 alanine missense substitution might be the main disease-causing mutation that damages CDH23 function and could be used as a genetic hearing loss marker for this particular Omani family.

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A novel missense mutation in the C2C domain of otoferlin causes profound hearing impairment in an Omani family with auditory neuropathy

Cited by 11 publications

References 35 publications

Auditory Neuropathy Spectrum Disorder (ANSD)—Clinical Characteristics and Pathogenic Variant Analysis of Three Nonsyndromic Deafness Families

Auditory Neuropathy Spectrum Disorder (ANSD)—Clinical Characteristics and Pathogenic Variant Analysis of Three Nonsyndromic Deafness Families

Cochlear proteins associated with noise-induced hearing loss: An update

In silico analysis of a novel causative mutation in Cadherin23 gene identified in an Omani family with hearing loss

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