Two Iranian families with a novel mutation in <i>GJB2</i> causing autosomal dominant nonsyndromic hearing loss

Bazazzadegan, Niloofar; Sheffield, Abraham M.; Sobhani, Masoomeh; Kahrizi, Kimia; Meyer, Nicole C.; Camp, Guy Van; Hilgert, Nele; Abedini, Seyedeh Sedigheh; Habibi, Farkhondeh; Daneshi, Ahmad; Nishimura, Carla; Avenarius, Matthew R.; Farhadi, Mohammad; Smith, Richard J.H.; Najmabadi, Hossein

doi:10.1002/ajmg.a.33209

Cited by 10 publications

(9 citation statements)

References 46 publications

(25 reference statements)

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“…It should be noted that a few mutations in the GJB2 gene have been associated with autosomal dominant inheritance (DFNA3), 37, 38, 39 which may be non-syndromic 40 or with associated skin features 41, 42, 43, 44, 45, 46, 47, 48 in syndromic forms of deafness such as Vohwinkel syndrome, Keratitis Ichthyosis Deafness, Bart Pumphrey syndrome, Palmo Plantar Keratoderma, and Hystrix-ichthyosis. These are particular mutations involving specific residues of the protein.…”

Section: Introductionmentioning

confidence: 99%

EMQN Best Practice guidelines for diagnostic testing of mutations causing non-syndromic hearing impairment at the DFNB1 locus

2013

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Section: Introductionmentioning

confidence: 99%

EMQN Best Practice guidelines for diagnostic testing of mutations causing non-syndromic hearing impairment at the DFNB1 locus

2013

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“…Unlike GJB2 recessive mutations in which the spectrum and phenotype-genotype correlations have been analyzed clearly, few studies of GJB2 dominant mutations have been reported. In addition, approximately two-thirds of dominant GJB2 mutations cause syndromic hearing loss associated with diverse skin disorders, whereas only the remaining one-third of mutations cause ADNSHL 4 . To date, more than thirty dominant mutations of GJB2 have been identified worldwide (The Human Gene Mutation Database, http://www.hgmd.cf.ac.uk), among which only 19 non-syndromic pathogenic variations have been described.…”

Section: Discussionmentioning

confidence: 99%

“…Connexin 26, which is expressed in the fibrocytes of the spiral ligament and spiral limbus, the basal cells of the stria vascularis, and the supporting cells in the Corti, plays a crucial role in K + homeostasis and intracellular signaling in the inner ear 12 . Most of the dominant mutations occur in the highly conserved first extracellular loop (E1) of connexin 26, which is critical for voltage gates and connexon-connexon docking 4 . The mutation c.524C > A identified in this study is located in the second extracellular loop (E2) region of connexin 26, which plays a crucial role in interacting with other connexin molecules in the same connexon.…”

Section: Discussionmentioning

confidence: 99%

A novel dominant GJB2 (DFNA3) mutation in a Chinese family

Wang

2017

The Journal of the Acoustical Society of America

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To decipher the phenotype and genotype of a Chinese family with autosomal dominant non-syndromic hearing loss (ADNSHL) and a novel dominant missense mutation in the GJB2 gene (DFNA3), mutation screening of GJB2 was performed on the propositus from a five-generation ADNSHL family through polymerase chain reaction amplification and Sanger sequencing. The candidate variation and the cosegregation of the phenotype were verified in all ascertained family members. Targeted genes capture and next-generation sequencing (NGS) were performed to explore additional genetic variations. We identified the novel GJB2 mutation c.524C > A (p.P175H), which segregated with high frequency and was involved in progressive sensorineural hearing loss. One subject with an additional c.235delC mutation showed a more severe phenotype than did the other members with single GJB2 dominant variations. Four patients diagnosed with noise-induced hearing loss did not carry this mutation. No other pathogenic variations or modifier genes were identified by NGS. In conclusion, a novel missense mutation in GJB2 (DFNA3), affecting the second extracellular domain of the protein, was identified in a family with ADNSHL.Mutations in the gene GJB2, which encodes the gap junction protein connexin 26, play a key role in hereditary hearing loss and represent the most common cause of non-syndromic hearing loss 1 . Variations in GJB2 may cause either autosomal dominant or recessive non-syndromic hearing loss (NSHL) as well as syndromic hearing loss (SHL). The inheritance pattern is ultimately determined by how the variation affects the expression and function of the connexin 26 protein. More than two hundred mutations in GJB2 (DFNB1, MIM220290) have been found to be related to autosomal recessive non-syndromic hearing loss 2 , whereas only nineteen GJB2 mutations have been associated with hereditary autosomal dominant non-syndromic deafness (DFNA3, MIM601544). Previous studies of dominant GJB2 mutations are rare and have been limited to cases or simplex families. In this study, via traditional PCR and Sanger sequencing, a novel GJB2 heterozygous mutation was identified in a Chinese family with autosomal dominant non-syndromic hearing loss (ADNSHL). Results Clinical description. From Family 304, a total of 32 family members, including 16 clinically affected and 16unaffected individuals, were included in this study (Fig. 1). Among the 16 affected cases, 4 subjects had explicit noise exposure history. In this family, the 12 affected members without noise exposure history showed symmetrical and bilateral non-syndromic sensorineural hearing loss, but no clear onset age was described (although the ages of identification were generally within childhood). The propositus (IV:2) was a 26-year-old male with bilateral progressive hearing loss when he first visited our outpatient clinic in 2004. The hearing impairment initially presented at high frequencies. He showed moderate or mild hearing loss at 0.5 kHz and 1 kHz and severe or profound hearing loss at 2 kHz, 4 kHz and ...

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“…In a typical situation, GJB2 mutations are inherited in an autosomal recessive pattern; however, there have been reported forms with a dominant pattern of inheritance (DFNA3), non--syndromic [3,4] or associated with skin lesions in the course of genetic conditions combined with deafness [5,6].…”

Section: Introductionmentioning

confidence: 99%