Genetics and Epigenetics of Hearing Loss

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 17204

Special Issue Editor


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Guest Editor
1. Institute for Maternal and Child Health—IRCCS, Burlo Garofolo, 34127 Trieste, Italy
2. Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy
Interests: clinical and molecular genetics; hereditary and multifactorial hearing loss
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Special Issue Information

Dear Colleagues, 

Hearing loss is one of the most common sensory impairment worldwide. Genetic factors account for 50–60% of all the cases with more than 200 genes described so far as having a role in the hearing process. Despite many efforts made in studying the genes involved, still, a lot of patients lack a final molecular diagnosis. Moreover, to date, very few studies have been focused on the role of epigenetic modifications in the development of deafness.

The aim of this Special Issue is to collect reviews and original articles on recent investigations of the molecular basis of hearing loss and describing the possible role of epigenetic factors in hearing-related processes and hearing loss. All manuscripts, both experimental and theoretical contributions, should highlight: 1) the molecular mechanisms at the level of single genes/proteins or their networks and 2) the benefit from the vast amounts of information that can be garnered from genetic and epigenetic work in this field.

Dr. Giorgia Girotto
Guest Editor

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Keywords

  • Genetics of hearing loss 
  • Epigenetics of hearing loss 
  • Genome wide association studies 
  • Next generation sequencing 
  • Large cohorts

Published Papers (6 papers)

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Research

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19 pages, 1306 KiB  
Article
Benefits of Exome Sequencing in Children with Suspected Isolated Hearing Loss
by Roxane Van Heurck, Maria Teresa Carminho-Rodrigues, Emmanuelle Ranza, Caterina Stafuzza, Lina Quteineh, Corinne Gehrig, Eva Hammar, Michel Guipponi, Marc Abramowicz, Pascal Senn, Nils Guinand, Helene Cao-Van and Ariane Paoloni-Giacobino
Genes 2021, 12(8), 1277; https://doi.org/10.3390/genes12081277 - 20 Aug 2021
Cited by 9 | Viewed by 3091
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Hearing Loss)
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15 pages, 1034 KiB  
Article
Hearing Function: Identification of New Candidate Genes Further Explaining the Complexity of This Sensory Ability
by Maria Pina Concas, Anna Morgan, Fabrizio Serra, Andries Paul Nagtegaal, Berthe C. Oosterloo, Sudha Seshadri, Nancy Heard-Costa, Guy Van Camp, Erik Fransen, Margherita Francescatto, Giancarlo Logroscino, Rodolfo Sardone, Nicola Quaranta, Paolo Gasparini and Giorgia Girotto
Genes 2021, 12(8), 1228; https://doi.org/10.3390/genes12081228 - 10 Aug 2021
Cited by 1 | Viewed by 3244
Abstract
To date, the knowledge of the genetic determinants behind the modulation of hearing ability is relatively limited. To investigate this trait, we performed Genome-Wide Association Study (GWAS) meta-analysis using genotype and audiometric data (hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 [...] Read more.
To date, the knowledge of the genetic determinants behind the modulation of hearing ability is relatively limited. To investigate this trait, we performed Genome-Wide Association Study (GWAS) meta-analysis using genotype and audiometric data (hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz, and pure-tone averages of thresholds at low, medium, and high frequencies) collected in nine cohorts from Europe, South-Eastern USA, Caucasus, and Central Asia, for an overall number of ~9000 subjects. Three hundred seventy-five genes across all nine analyses were tagged by single nucleotide polymorphisms (SNPs) reaching a suggestive p-value (p < 10−5). Amongst these, 15 were successfully replicated using a gene-based approach in the independent Italian Salus in the Apulia cohort (n = 1774) at the nominal significance threshold (p < 0.05). In addition, the expression level of the replicated genes was assessed in published human and mouse inner ear datasets. Considering expression patterns in humans and mice, eleven genes were considered particularly promising candidates for the hearing function: BNIP3L, ELP5, MAP3K20, MATN2, MTMR7, MYO1E, PCNT, R3HDM1, SLC9A9, TGFB2, and YTHDC2. These findings represent a further contribution to our understanding of the genetic basis of hearing function and its related diseases. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Hearing Loss)
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9 pages, 2493 KiB  
Communication
Identification of a Homozygous PEX26 Mutation in a Heimler Syndrome Patient
by Youn Jung Kim, Yuichi Abe, Young-Jae Kim, Yukio Fujiki and Jung-Wook Kim
Genes 2021, 12(5), 646; https://doi.org/10.3390/genes12050646 - 26 Apr 2021
Cited by 7 | Viewed by 2123
Abstract
This study aimed to identify the molecular genetic etiology of an 8-year-old boy with amelogenesis imperfecta in permanent dentition. Bilateral cochlear implants were placed due to sensorineural hearing loss, and there was no other family member with a similar phenotype. Peripheral blood samples [...] Read more.
This study aimed to identify the molecular genetic etiology of an 8-year-old boy with amelogenesis imperfecta in permanent dentition. Bilateral cochlear implants were placed due to sensorineural hearing loss, and there was no other family member with a similar phenotype. Peripheral blood samples were collected with the understanding and written consent of the participating family members. A constitutional chromosome study was performed for the proband. Genomic DNA was isolated, and whole exome sequencing was performed. A series of bioinformatic analyses were performed with the obtained paired-end sequencing reads, and the variants were filtered and annotated with dbSNP147. There was no abnormality in the constitutional chromosome study. Whole exome sequencing analysis with trio samples identified a homozygous mutation (c.506T>C, p. (Leu169Pro)) in the PEX26 gene. We verified temperature sensitivity (ts)” of patient-derived Pex26-L169P by expression in pex26 CHO mutant ZP167 cells to determine the effect of the L169P mutation on Pex26 function. The L169P mutation causes a mild ts-cellular phenotype representing the decreased peroxisomal import of catalase. This study supports the finding that the recessive mutations in PEX26 are associated with Heimler syndrome and demonstrates the importance of an early and correct diagnosis. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Hearing Loss)
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Review

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22 pages, 1907 KiB  
Review
Insulin-like Growth Factor 1 Signaling in Mammalian Hearing
by Ángela García-Mato, Blanca Cervantes, Silvia Murillo-Cuesta, Lourdes Rodríguez-de la Rosa and Isabel Varela-Nieto
Genes 2021, 12(10), 1553; https://doi.org/10.3390/genes12101553 - 29 Sep 2021
Cited by 12 | Viewed by 3304
Abstract
Insulin-like growth factor 1 (IGF-1) is a peptide hormone belonging to the insulin family of proteins. Almost all of the biological effects of IGF-1 are mediated through binding to its high-affinity tyrosine kinase receptor (IGF1R), a transmembrane receptor belonging to the insulin receptor [...] Read more.
Insulin-like growth factor 1 (IGF-1) is a peptide hormone belonging to the insulin family of proteins. Almost all of the biological effects of IGF-1 are mediated through binding to its high-affinity tyrosine kinase receptor (IGF1R), a transmembrane receptor belonging to the insulin receptor family. Factors, receptors and IGF-binding proteins form the IGF system, which has multiple roles in mammalian development, adult tissue homeostasis, and aging. Consequently, mutations in genes of the IGF system, including downstream intracellular targets, underlie multiple common pathologies and are associated with multiple rare human diseases. Here we review the contribution of the IGF system to our understanding of the molecular and genetic basis of human hearing loss by describing, (i) the expression patterns of the IGF system in the mammalian inner ear; (ii) downstream signaling of IGF-1 in the hearing organ; (iii) mouse mutations in the IGF system, including upstream regulators and downstream targets of IGF-1 that inform cochlear pathophysiology; and (iv) human mutations in these genes causing hearing loss. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Hearing Loss)
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Other

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9 pages, 3111 KiB  
Brief Report
Identification and Computational Analysis of Rare Variants of Known Hearing Loss Genes Present in Five Deaf Members of a Pakistani Kindred
by Irum Badshah Saleem, Muhammad Shareef Masoud, Muhammad Qasim, Muhammad Ali and Zubair M. Ahmed
Genes 2021, 12(12), 1940; https://doi.org/10.3390/genes12121940 - 30 Nov 2021
Cited by 2 | Viewed by 2262
Abstract
Hearing loss (HL) is the most common neurosensory defect in humans that affects the normal communication. Disease is clinically and genetically heterogeneous, rendering challenges for the molecular diagnosis of affected subjects. This study highlights the phenotypic and genetic complexity of inherited HL in [...] Read more.
Hearing loss (HL) is the most common neurosensory defect in humans that affects the normal communication. Disease is clinically and genetically heterogeneous, rendering challenges for the molecular diagnosis of affected subjects. This study highlights the phenotypic and genetic complexity of inherited HL in a large consanguineous Pakistan kindred. Audiological evaluation of all affected individuals revealed varying degree of mild to profound sensorineural HL. Whole exome (WES) of four family members followed by Sanger sequencing revealed candidate disease-associated variants in five known deafness genes: GJB2 (c.231G>A; p.(Trp77 *)), SLC26A4 (c.1337A>G; p.(Gln446Arg)), CDH23 (c.2789C>T; p.(Pro930Leu)), KCNQ4 (c.1672G>A; p.(Val558Met)) and MPDZ (c.4124T>C; p.(Val1375Ala)). All identified variants replaced evolutionary conserved residues, were either absent or had low frequencies in the control databases. Our in silico and 3-Dimensional (3D) protein topology analyses support the damaging impact of identified variants on the encoded proteins. However, except for the previously established “pathogenic” and “likely pathogenic” categories for the c.231G>A (p.(Trp77 *)) allele of GJB2 and c.1377A>G (p.(Gln446Arg)) of SLC26A4, respectively, all the remaining identified variants were classified as “uncertain significance” based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant pathogenicity guidelines. Our study highlights the complexity of genetic traits in consanguineous families, and the need of combining the functional studies even with the comprehensive profiling of multiple family members to improve the genetic diagnosis in complex inbred families. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Hearing Loss)
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9 pages, 1680 KiB  
Case Report
Non-Syndromic Autosomal Dominant Hearing Loss: The First Italian Family Carrying a Mutation in the NCOA3 Gene
by Paola Tesolin, Anna Morgan, Michela Notarangelo, Rocco Pio Ortore, Maria Pina Concas, Angelantonio Notarangelo and Giorgia Girotto
Genes 2021, 12(7), 1043; https://doi.org/10.3390/genes12071043 - 6 Jul 2021
Cited by 3 | Viewed by 2260
Abstract
Hearing loss (HL) is the most frequent sensory disorder, affecting about 1–3 per 1000 live births, with more than half of the cases attributable to genetic causes. Despite the fact that many HL causative genes have already been identified, current genetic tests fail [...] Read more.
Hearing loss (HL) is the most frequent sensory disorder, affecting about 1–3 per 1000 live births, with more than half of the cases attributable to genetic causes. Despite the fact that many HL causative genes have already been identified, current genetic tests fail to provide a diagnosis for about 40% of the patients, suggesting that other causes still need to be discovered. Here, we describe a four-generation Italian family affected by autosomal dominant non-syndromic hearing loss (ADNSHL), in which exome sequencing revealed a likely pathogenic variant in NCOA3 (NM_181659.3, c.2909G>C, p.(Gly970Ala)), a gene recently described as a novel candidate for ADNSHL in a Brazilian family. A comparison between the two families highlighted a series of similarities: both the identified variants are missense, localized in exon 15 of the NCOA3 gene and lead to a similar clinical phenotype, with non-syndromic, sensorineural, bilateral, moderate to profound hearing loss, with a variable age of onset. Our findings (i.e., the identification of the second family reported globally with HL caused by a variant in NCOA3) further support the involvement of NCOA3 in the etiopathogenesis of ADNSHL, which should, thus, be considered as a new gene for autosomal dominant non-syndromic hearing loss. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Hearing Loss)
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