<i>WFS1</i> and <i>GJB2</i> mutations in patients with bilateral low‐frequency sensorineural hearing loss

Kasakura-Kimura, Natsuko; Masuda, Masataka; Mutai, Hideki; Masuda, Sawako; Morimoto, Noriko; Ogahara, Noboru; Misawa, Hayato; Sakamoto, Hirokazu; Saito, Koichiro; Matsunaga, Tatsuo

doi:10.1002/lary.26528

Cited by 10 publications

(8 citation statements)

References 38 publications

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“…This is an indication of the urgent need to implement this GJB2 -p.R143W testing in patients with HI clinical practice in Ghana. The p.R143W mutation has also been reported in patients with HI in Japan (Zheng et al, 2015; Kasakura-Kimura et al, 2017), South Korea (Kim et al, 2016), and China (Luo et al, 2017). In addition, we report a variant previously described as Mayan: founder GJB2 nonsense mutation (p.W44*) in a Ghanaian family.…”

Section: Discussionmentioning

confidence: 91%

GJB2 and GJB6 Mutations in Non-Syndromic Childhood Hearing Impairment in Ghana

et al. 2019

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Our study aimed to investigate GJB2 (connexin 26) and GJB6 (connexin 30) mutations associated with non-syndromic childhood hearing impairment (HI) as well as the environmental causes of HI in Ghana. Medical reports of 1,104 students attending schools for the deaf were analyzed. Families segregating HI, as well as isolated cases of HI of putative genetic origin were recruited. DNA was extracted from peripheral blood followed by Sanger sequencing of the entire coding region of GJB2. Multiplex PCR and Sanger sequencing were used to analyze the prevalence of GJB6-D3S1830 deletion. Ninetyseven families segregating HI were identified, with 235 affected individuals; and a total of 166 isolated cases of putative genetic causes, were sampled from 11 schools for the deaf in Ghana. The environmental factors, particularly meningitis, remain a major cause of HI impairment in Ghana. The male/female ratio was 1.49. Only 59.6% of the patients had their first comprehensive HI test between 6 to 11 years of age. Nearly all the participants had sensorineural HI (99.5%; n = 639). The majority had pre-lingual HI (68.3%, n = 754), of which 92.8% were congenital. Pedigree analysis suggested autosomal recessive inheritance in 96.9% of the familial cases. GJB2-R143W mutation, previously reported as founder a mutation in Ghana accounted for 25.9% (21/81) in the homozygous state in familial cases, and in 7.9% (11/140) of non-familial non-syndromic congenital HI cases, of putative genetic origin. In a control population without HI, we found a prevalent of GJB2-R143W carriers of 1.4% (2/145), in the heterozygous state. No GJB6-D3S1830 deletion was identified in any of the HI patients. GJB2-R143W mutation accounted for over a quarter of familial non-syndromic HI in Ghana and should be investigated in clinical practice. The large connexin 30 gene deletion (GJB6-D3S1830 deletion) does not account for of congenital non-syndromic HI in Ghana. There is a need to employ next generation sequencing approaches and functional genomics studies to identify the other genes involved in most families and isolated cases of HI in Ghana.

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Section: Discussionmentioning

confidence: 91%

GJB2 and GJB6 Mutations in Non-Syndromic Childhood Hearing Impairment in Ghana

et al. 2019

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“…One of the two LMX1A variants identified in this study occurred de novo. Also, we identified de novo variants with a dominant effect to explain four of 67 cases for whom a genetic diagnosis was established by testing a deafness gene panel and Kasakura-Kimura et al ( 2017 ) identified de novo variants as the cause of dominantly inherited HI in two of 74 ‘solved’ cases (Kasakura-Kimura et al 2017 ; Zazo Seco et al 2015 ). Interestingly, also for retinitis pigmentosa that displays very high genetic heterogeneity as does HI, the underlying genetic defect was found to be a de novo variant in 3 of 28 individuals without family history of the disease (Neveling et al 2012 ).…”

Section: Discussionmentioning

confidence: 96%

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

et al. 2018

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Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.Electronic supplementary materialThe online version of this article (10.1007/s00439-018-1880-5) contains supplementary material, which is available to authorized users.

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“…Pathogenic variants of the WFS1 gene (OMIM:606210) may cause Wolfram syndrome, Wolfram-like syndrome, or autosomal dominant non-syndromic DFNA6/14/38 [ 31 , 32 , 33 , 34 , 35 ]. Wolframin (WFS1), encoded by WFS1 , is an endoglycosidase H-sensitive membrane glycoprotein localized in the endoplasmic reticulum that is involved in the regulation of intracellular calcium homeostasis [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Nine (50%) patients underwent bilateral implantation, one of whom received bilateral simultaneous implantation. The preoperative hearing threshold was 88.2 ± 14.5 (57.5-106.3) dBHL, and the CI-aided hearing threshold was 25.6 ± 4.1 (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) dBHL. The median CAP and SIR scores at the latest follow-up were 7 (range, 5-7) and 5 (range, 2-5), respectively, indicating that these patients showed excellent outcomes.…”

Section: Outcomes In Ansd Patients With Biallelic Otof Variantsmentioning

confidence: 99%

Cochlear Implantation Outcomes in Patients with Auditory Neuropathy Spectrum Disorder of Genetic and Non-Genetic Etiologies: A Multicenter Study

Lin

et al. 2022

Biomedicines

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With diverse etiologies and clinical features, the management of pediatric auditory neuropathy spectrum disorder (ANSD) is often challenging, and the outcomes of cochlear implants (CIs) are variable. This study aimed to investigate CI outcomes in pediatric patients with ANSD of different etiologies. Thirty-six children with ANSD who underwent cochlear implantation between 2001 and 2021 were included. Comprehensive etiological analyses were conducted, including a history review, next-generation sequencing-based genetic examinations, and imaging studies using high-resolution computed tomography and magnetic resonance imaging. Serial behavioral and speech audiometry were performed before and after surgery, and the outcomes with CI were evaluated using the Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores. By etiology, 18, 1, 1, and 10 patients had OTOF-related, WFS1-related, OPA1-related, and cochlear nerve deficiency (CND)-related ANSD, respectively. Six patients had no definite etiology. The average CI-aided behavioral threshold was 28.3 ± 7.8 dBHL, and those with CND-related ANSD were significantly worse than OTOF-related ANSD. The patients’ median CAP and SIR scores were 6 and 4, respectively. Favorable CI outcomes were observed in patients with certain etiologies of ANSD, particularly those with OTOF (CAP/SIR scores 5–7/2–5), WFS1 (CAP/SIR score 6/5), and OPA1 variants (CAP/SIR score 7/5). Patients with CND had suboptimal CI outcomes (CAP/SIR scores 2–6/1–3). Identifying the etiologies in ANSD patients is crucial before surgery and can aid in predicting prognoses.

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WFS1 and GJB2 mutations in patients with bilateral low‐frequency sensorineural hearing loss

Abstract: 4. Laryngoscope, 127:E324-E329, 2017.

Cited by 10 publications

References 38 publications

GJB2 and GJB6 Mutations in Non-Syndromic Childhood Hearing Impairment in Ghana

GJB2 and GJB6 Mutations in Non-Syndromic Childhood Hearing Impairment in Ghana

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Cochlear Implantation Outcomes in Patients with Auditory Neuropathy Spectrum Disorder of Genetic and Non-Genetic Etiologies: A Multicenter Study

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