Genetic Epidemiology and Clinical Features of Hereditary Hearing Impairment in the Taiwanese Population

Wu, Chen‐Chi; Tsai, Chung-You; Lin, Yi‐Hsin; Chen, Pey-Yu; Lin, Pei‐Hsuan; Wu, Che‐Ming; Lin, Yin-Hung; Lee, Chee-Yee; Erdenechuluun, Jargalkhuu; Liu, Tien‐Chen; Chen, Pei‐Lung

doi:10.3390/genes10100772

Cited by 38 publications

(34 citation statements)

References 94 publications

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“…The presence of OAE is main reason for missing OTOF-related ANSD at NBHS. Similar to our result, it was reported that 75% of OTOF-related patients improperly passed NBHS in a previous study (Wu et al 2019). The risk of using OAE for NBHS has been discussed from the point of view of its inability in detecting ANSD.…”

Section: Discussionsupporting

confidence: 93%

Detailed Clinical Features and Genotype-Phenotype Correlation in an OTOF-Related Hearing Loss Cohort in Japan

Iwasa¹,

Nishio²,

Yoishimura³

et al. 2021

Preprint

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OTOF is one of the most frequent causes of hereditary hearing loss and a main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in the patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 65 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.8%) showed a “typical” phenotype, prelingual and severe-to-profound hearing loss. Forty-seven patients (72.3%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39dB with cochlear implant and a CAP scale (Categories of Auditory Performance) level 6 or better. Although truncating mutations and p.R1939Q were clearly related to severe phenotype, almost half of patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.H513R, p.I1573T and p.E1910K showed “true” auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

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Section: Discussionsupporting

confidence: 93%

Detailed Clinical Features and Genotype-Phenotype Correlation in an OTOF-Related Hearing Loss Cohort in Japan

Iwasa¹,

Nishio²,

Yoishimura³

et al. 2021

Preprint

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“…Patient 27 is of Italian origin and patient 29 has French origins, thus suggesting that TMPRSS3 mutations might be more frequently involved in non-syndromic HL than reported in the literature, even in Caucasian patients [11,45,69]. As shown previously, the local epidemiology and diagnostic rate vary widely regarding ethnicity [11,[70][71][72]. Geneva is a city located at the crossroads of Europe and is known for its mixed ethnicity and thus our rates probably do not reflect a classical Western Europe Caucasian population epidemiology.…”

Section: Discussionmentioning

confidence: 69%

Benefits of Exome Sequencing in Children with Suspected Isolated Hearing Loss

Heurck

Carminho‐Rodrigues

Ranza

et al. 2021

Genes

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Purpose: Hearing loss is characterized by an extensive genetic heterogeneity and remains a common disorder in children. Molecular diagnosis is of particular benefit in children, and permits the early identification of clinically-unrecognized hearing loss syndromes, which permits effective clinical management and follow-up, including genetic counselling. Methods: We performed whole-exome sequencing with the analysis of a panel of 189 genes associated with hearing loss in a prospective cohort of 61 children and 9 adults presenting mainly with isolated hearing loss. Results: The overall diagnostic rate using exome sequencing was 47.2% (52.5% in children; 22% in adults). In children with confirmed molecular results, 17/32 (53.2%) showed autosomal recessive inheritance patterns, 14/32 (43.75%) showed an autosomal dominant condition, and one case had X-linked hearing loss. In adults, the two patients showed an autosomal dominant inheritance pattern. Among the 32 children, 17 (53.1%) had nonsyndromic hearing loss and 15 (46.7%) had syndromic hearing loss. One adult was diagnosed with syndromic hearing loss and one with nonsyndromic hearing loss. The most common causative genes were STRC (5 cases), GJB2 (3 cases), COL11A1 (3 cases), and ACTG1 (3 cases). Conclusions: Exome sequencing has a high diagnostic yield in children with hearing loss and can reveal a syndromic hearing loss form before other organs/systems become involved, allowing the surveillance of unrecognized present and/or future complications associated with these syndromes.

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“…In this study, we reported a third cluster of familial TSAN, which includes three cases with two variants of the OTOF gene (which encodes otoferlin protein), c.5098G > C (p.Glu1700Gln) and c.4882C > A (p.Pro1628Thr). The reasons why both variants were considered part of the cause of TSAN in this family are as follows: (1) both are missense variants affecting residues that are completely preserved among different species; (2) p.Glu1700Gln has been shown to be pathogenic (Chiu et al, 2010;Chen et al, 2018;Qiu et al, 2019;Wu et al, 2019); (3) p.Pro1628Thr, which is reported here for the first time, was absent in 200 normal controls and has a very low allele frequency in a public database (8.67 × 10 −6 in ExAC); and (4) both variants strongly co-segregated with the TSAN phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…In the three cases (with the identical twin brothers regarded as representing one case) involving subjects who were TSAN patients, the subjects were compound heterozygotes for the two variants, and both parents were unaffected and heterozygous (Figure 1). The c.5098G > C variant, which occurred in exon 40 and was inherited from the unaffected mother (I-2), resulted in a glutamic acid-to-glutamine substitution at position 1,700 and has been previously reported as a pathogenic allele (Chiu et al, 2010;Chen et al, 2018;Qiu et al, 2019;Wu et al, 2019). The other variant, c.4882C > A, which was located in exon 39 and passed on from the clinically normal father (I-1), resulted in a single amino acid change from a proline to a threonine at position 1,628 in otoferlin.…”

Section: Variant Validation and Analysismentioning

confidence: 99%

Familial Temperature-Sensitive Auditory Neuropathy: Distinctive Clinical Courses Caused by Variants of the OTOF Gene

Zhu

Gao³

et al. 2021

Front. Cell Dev. Biol.

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Objective: To investigate the clinical course and genetic etiology of familial temperature-sensitive auditory neuropathy (TSAN), which is a very rare subtype of auditory neuropathy (AN) that involves an elevation of hearing thresholds due to an increase in the core body temperature, and to evaluate the genotype–phenotype correlations in a family with TSAN.Methods: Six members of a non-consanguineous Chinese family, including four siblings complaining of communication difficulties when febrile, were enrolled in this study. The clinical and audiological profiles of the four siblings were fully evaluated during both febrile and afebrile episodes, and the genetic etiology of hearing loss (HL) was explored using next-generation sequencing (NGS) technology. Their parents, who had no complaints of fluctuating HL due to body temperature variation, were enrolled for the genetics portion only.Results: Audiological tests during the patients’ febrile episodes met the classical diagnostic criteria for AN, including mild HL, poor speech discrimination, preserved cochlear microphonics (CMs), and absent auditory brainstem responses (ABRs). Importantly, unlike the pattern observed in previously reported cases of TSAN, the ABRs and electrocochleography (ECochG) signals of our patients improved to normal during afebrile periods. Genetic analysis identified a compound heterozygous variant of the OTOF gene (which encodes the otoferlin protein), including one previously reported pathogenic variant, c.5098G > C (p.Glu1700Gln), and one novel variant, c.4882C > A (p.Pro1628Thr). Neither of the identified variants affected the C2 domains related to the main function of otoferlin. Both variants faithfully cosegregated with TSAN within the pedigree, suggesting that OTOF is the causative gene of the autosomal recessive trait segregation in this family.Conclusion: The presence of CMs with absent (or markedly abnormal) ABRs is a reliable criterion for diagnosing AN. The severity of the phenotype caused by dysfunctional neurotransmitter release in TSAN may reflect variants that alter the C2 domains of otoferlin. The observations from this study enrich the current understanding of the phenotype and genotype of TSAN and may lay a foundation for further research on its pathogenesis.

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Genetic Epidemiology and Clinical Features of Hereditary Hearing Impairment in the Taiwanese Population

Cited by 38 publications

References 94 publications

Detailed Clinical Features and Genotype-Phenotype Correlation in an OTOF-Related Hearing Loss Cohort in Japan

Detailed Clinical Features and Genotype-Phenotype Correlation in an OTOF-Related Hearing Loss Cohort in Japan

Benefits of Exome Sequencing in Children with Suspected Isolated Hearing Loss

Familial Temperature-Sensitive Auditory Neuropathy: Distinctive Clinical Courses Caused by Variants of the OTOF Gene

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