scholarly journals TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dominika Oziębło ◽  
Marcin L. Leja ◽  
Michal Lazniewski ◽  
Anna Sarosiak ◽  
Grażyna Tacikowska ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
High Frequencies ◽  
Important Contributor ◽  
Pathogenic Variants ◽  
Age Related ◽  
Functional Consequences ◽  
Protein Variants ◽  
Autosomal Recessive Manner

AbstractSeveral TBC1D24 variants are causally involved in the development of profound, prelingual hearing loss (HL) and different epilepsy syndromes inherited in an autosomal recessive manner. Only two TBC1D24 pathogenic variants have been linked with postlingual progressive autosomal dominant HL (ADHL). To determine the role of TBC1D24 in the development of ADHL and to characterize the TBC1D24-related ADHL, clinical exome sequencing or targeted multigene (n = 237) panel were performed for probands (n = 102) from multigenerational ADHL families. In four families, TBC1D24-related HL was found based on the identification of three novel, likely pathogenic (c.553G>A, p.Asp185Asn; c.1460A>T, p. His487Leu or c.1461C>G, p.His487Gln) and one known (c.533C>T, p.Ser178Leu) TBC1D24 variant. Functional consequences of these variants were characterized by analyzing the proposed homology models of the human TBC1D24 protein. Variants not only in the TBC (p.Ser178Leu, p.Asp185Asn) but also in the TLDc domain (p.His487Gln, p.His487Leu) are involved in ADHL development, the latter two mutations probably affecting interactions between the domains. Clinically, progressive HL involving mainly mid and high frequencies was observed in the patients (n = 29). The progression of HL was calculated by constructing age-related typical audiograms. TBC1D24-related ADHL originates from the cochlear component of the auditory system, becomes apparent usually in the second decade of life and accounts for approximately 4% of ADHL cases. Given the high genetic heterogeneity of ADHL, TBC1D24 emerges as an important contributor to this type of HL.

Molecular genetic diagnostics of Bardet-Biedl syndrome with an MPS-panel

2021 ◽  
pp. 26-35
Author(s):  
М.Д. Орлова ◽  
П. Гундорова ◽  
А.В. Поляков
Keyword(s):  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Autosomal Recessive Disorder ◽  
Genetic Diagnostics ◽  
Bardet Biedl Syndrome ◽  
Pathogenic Variants ◽  
Development Delay ◽  
Molecular Genetic Diagnostics ◽  
First Time

Синдром Барде-Бидля - аутосомно-рецессивное заболевание, характеризующееся ожирением, пигментной дегенерацией сетчатки, полидактилией, задержкой психоречевого развития и структурными повреждениями почек. В работе представлены результаты применения МПС-панели, включающей кодирующие последовательности и прилегающие интронные области 21 гена, ассоциированного с синдромом Барде-Бидля. Впервые была проведена молекулярно-генетическая диагностика в группе из сорока российских пациентов с синдромом Барде-Бидля из неродственных семей. В результате исследования удалось подтвердить диагноз молекулярно-генетическим методом у 40% пациентов (n=16). В генах BBS1, BBS7 и BBS10 встретились повторяющиеся варианты. Частота встречаемости патогенных и вероятно патогенных вариантов в генах BBS1 и BBS10 у российских пациентов соответствует зарубежным данным. Варианты в гене BBS7 встретились у пяти человек, у четырех из них был обнаружен патогенный вариант c.1967_1968delTAinsC, не встречающийся в других популяциях. Результаты, представленные в статье, показывают значительный вклад в заболеваемость синдромом Барде-Бидля в российской популяции патогенных вариантов в гене BBS7. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by obesity, retinitis pigmentosa, polydactyly, development delay, and structural kidney defects. This study shows the results of using an MPS panel that includes coding sequences and intronic areas of 21 genes associated with Bardet-Biedl syndrome. For the first time molecular genetic testing has been provided for the group of 40 Russian patiens with Bardet-Biedl syndrome from unrelated families. As a result of the testing, diagnoses were confirmed for 40% of the patients (n=16). The genes BBS1, BBS7, BBS10 had recurrent variants. The frequency of pathogenic and likely pathogenic variants in the genes BBS1 and BBS10 among Russian patients matches the research data in other countries. Variants in the BBS7 gene were found for five people, four of them had a pathogenic variant c.1967_1968delTAinsC, which is not present among other populations. Results provided in this article show the significant role of pathogenic variants in the BBS7 gene in patients with Bardet-Biedl syndrome in Russian population.

scholarly journals Association of Age-Related Hearing Loss with Cognitive Decline

2020 ◽  
Vol 63 (4) ◽  
pp. 145-153
Author(s):  
Juyong Chung
Keyword(s):  
Hearing Loss ◽  
Cognitive Decline ◽  
Cochlear Implants ◽  
Hearing Aids ◽  
Microvascular Disease ◽  
Single Mechanism ◽  
Hearing Aid Use ◽  
Age Related ◽  
Age Related Hearing Loss

A number of studies have demonstrated a significant association between age-related hearing loss (ARHL) and cognitive decline. However their relationship is not clear. In this review, we focused on the etiological mechanisms between ARHL and cognitive decline to explain the nature of this relationship: 1) causal mechanisms (e.g., cognitive load hypothesis, cascade hypothesis); 2) common cause mechanisms (e.g., microvascular disease); 3) overdiagnosis or harbinger hypothesis. We conclude that no single mechanism is sufficient and hearing and cognition related to each other in several different ways. In addition, we reviewed the effectiveness of hearing intervention (e.g., hearing aids and cochlear implants) on cognition function, and the role of hearing aid use and cochlear implant depends on the relevant mechanism.

scholarly journals Estimation of auditory threshold in an extended frequency range in elderly people

2019 ◽  
Vol 4 (4) ◽  
pp. 4-7
Author(s):  
Lubov V. Aizenshtadt ◽  
Tatyana Yu. Vladimirova ◽  
Alexandr V. Kurenkov ◽  
Anastasia M. Kashapova
Keyword(s):  
Hearing Loss ◽  
Age Group ◽  
Auditory Function ◽  
Frequency Range ◽  
Auditory Thresholds ◽  
High Frequencies ◽  
Age Related ◽  
Hearing Thresholds ◽  
Extended Frequency Range ◽  
Extended Frequency

Objectives - to study hearing thresholds at high frequencies in elderly and senile patients, taking into account the age norm and the presence of comorbid diseases. Material and methods. 111 patients aged from 50 to 97 years (mean age 70.5 ± 2.1) were examined, their age, auditory function, and concomitant diseases were also registered. Results. The measured average auditory thresholds at high frequencies, if compared to the age-related standards for auditory sensitivity, have revealed an underestimated hearing loss in 12.6% of patients. The presence of concomitant diseases has a significant impact on the development of chronic sensorineural hearing loss in each age group. Conclusion. Audiometry in an extended frequency range in elderly patients with concurrent diseases can improve the hearing examination algorithm.

scholarly journals Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis

2020 ◽  
Vol 117 (49) ◽  
pp. 31278-31289
Author(s):  
Sophie Boucher ◽  
Fabienne Wong Jun Tai ◽  
Sedigheh Delmaghani ◽  
Andrea Lelli ◽  
Amrit Singh-Estivalet ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hearing Loss ◽  
Early Onset ◽  
Cell Biology ◽  
Public Health Issue ◽  
Phenotypic Variance ◽  
Pathogenic Variants ◽  
Age Related ◽  
Small Effect Size ◽  
Age Related Hearing Loss

Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P= 0.001); half were previously unknown (AF < 0.000002).MYO6,MYO7A,PTPRQ, andTECTAvariants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also establishedTmc1N321I/+mice, carrying theTMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

Role of general practitioners in managing age‐related hearing loss

2010 ◽  
Vol 192 (1) ◽  
pp. 20-23 ◽  
Author(s):  
Julie M Schneider ◽  
Bamini Gopinath ◽  
Catherine M McMahon ◽  
Helena C Britt ◽  
Christopher M Harrison ◽  
...  
Keyword(s):  
Hearing Loss ◽  
General Practitioners ◽  
Age Related ◽  
Age Related Hearing Loss

scholarly journals Audiological features in Serbian patients with hearing impairment identified with c.35delG in the GJB2 gene

2021 ◽  
pp. 98-98
Author(s):  
Bojana Dobric ◽  
Danijela Radivojevic ◽  
Jovana Jecmenica ◽  
Vassos Neocleous ◽  
Pavlos Fanis ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hearing Impairment ◽  
Autosomal Recessive ◽  
Gjb2 Gene ◽  
Compound Heterozygous ◽  
Heterozygous State ◽  
Phenotype Correlation ◽  
Pathogenic Variants ◽  
Environmental Causes ◽  
35Delg Mutation

Introduction/Objective. Hearing impairment (HI) is the most common sensorineural disorder with an incidence of 1/700-1000 newborns. Variants in the GJB2 gene are the major cause of autosomal recessive nonsyndromic sensorineural hearing loss (ARNSHL). The degree of HI in patients with detected mutations in GJB2 gene ranges from mild to profound. The aim of this study was to determine possible genotype-phenotype association between audiometric characteristics and detected genotypes in ARNSHL patients from Serbia. Methods. Ninety-two patients with ARNSHL underwent genetic analysis with PCR-ARMS and sequencing of the GJB2 gene. Audiological analyses were obtained in all patients using a combination of several methods to estimate the degree of hearing loss. Results. Audiological analysis performed in the 92 probands showed moderate to profound range of hearing loss. All identified pathogenic variants accounted for 42.39% of the mutant alleles (78/184 alleles), with the c.35delG mutation being the most frequent (30.43%). Genotype-phenotype correlation in an isolated group of 37 patients bearing c.35delG in the homozygous, compound heterozygous or heterozygous state. In this group the majority of patients (30/37, 81.08%) exhibited severe to profound hearing deficit. Conclusion. Association between genotype and the degree of hearing impairment in patients analyzed in this study demonstrated that patients with bi-allelic truncating mutations i.e. c.35delG, associate with the more severe hearing loss when compared with those identified with only one affected allele. The various degrees of hearing impairment observed in heterozygous patients could be explained by the presence of an undetected second mutation or other modifier genes or environmental causes.

scholarly journals Novel Loss-of-Function Mutations in COCH Cause Autosomal Recessive Nonsyndromic Deafness

2020 ◽  
Author(s):  
Kevin T Booth ◽  
Amama Ghaffar ◽  
Muhammad Rashid ◽  
Luke T Hovey ◽  
Mureed Hussain ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Rna Splicing ◽  
Autosomal Recessive ◽  
Dominant Negative ◽  
Nonsyndromic Hearing Loss ◽  
Loss Of Function ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Exon Splicing ◽  
Coding Variants

AbstractCOCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly deafness in mice and humans. Two forms of deafness are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used mini-gene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA-splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA-splicing, and highlights the need to investigate the effect of coding variants on RNA-splicing.

scholarly journals The role of the General Practitioner in managing age-related hearing loss: Perspectives of General Practitioners, patients and practice staff

2020 ◽  
Author(s):  
Rebecca Jane Bennett ◽  
Susan Fletcher ◽  
Nicole Conway ◽  
Caitlin Barr
Keyword(s):  
Hearing Loss ◽  
General Practitioner ◽  
Concept Mapping ◽  
Practice Nurses ◽  
Online Portal ◽  
Age Related ◽  
Mapping Techniques ◽  
Age Related Hearing Loss ◽  
Instrumental Role

Abstract Background For people with hearing loss, the General Practitioner (GP) can play an instrumental role in early detection of hearing loss as well as guiding appropriate and timely choices for addressing hearing concerns. The aim of this study was to generate a conceptual framework for understanding the role of the GP in managing age-related hearing loss. Methods Concept mapping techniques were used to gather the perspectives of GPs (n = 8), adults with hearing loss (n = 22), and professionals working with GPs (n = 5), in Australia. Participants generated statements describing the role of the GP in managing age-related hearing loss, and then grouped the statements to identify key themes, via an online portal. Results Ninety-eight items describing the role of the GP in managing age-related hearing loss were identified across six concepts: 1) Determine - Diagnose - Discuss, 2) Ask - Assess - Act, 3) Know - Refer - Coordinate, 4) Inform - Advise - Partner, 5) Educate - Strategise - Encourage, 6) Reassure - Support - Empower. Conclusions The role of the GP in managing age-related hearing loss is multifaceted and requires partnership that motivates and empowers patients’ to overcome their hearing concerns. Enlisting the help of Practice Nurses, Practice Managers and local audiologists could help GPs improve their hearing loss detection and intervention rates.

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