Genetics of Hearing Loss

A special issue of Audiology Research (ISSN 2039-4349).

Deadline for manuscript submissions: closed (15 September 2021) | Viewed by 48757

Special Issue Editors


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Guest Editor
Department of Neurosciences (DNS), Otolaryngology Section, Padova University, Padova, Italy
Interests: hearing disorders; otology; cochlear implants; audiology; genetics
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Clinical Genetics Unit, Department of Women’s and Children’s Health, University of Padova, 35128 Padova, Italy
Interests: clinical genetics; clinical teratology; molecular genetics

Special Issue Information

Dear colleague,

It is my pleasure to invite you to submit an article for a Special Issue on “Genetics of Hearing Loss.”

Fifty years have passed since Walter Nance’s paper “Genetic counseling for the hearing impaired” was published in International Journal of Audiology (1971) [1], followed 5 years later by the publication of the fundamental book by Bruce Konigsmark (volume completed by Robert J. Gorlin after Bruce’s early disappearance in 1973), titled Genetic and Metabolic Deafness (W B Saunders Co, 1976) [2].

Many discoveries that have revolutionized our approach to children with hearing loss have been made in these 50 years. With regard to genetics, the first non-syndromic deafness locus was mapped in 1988 studying families showing X-linked inheritance (DFNX2) [3,4]; the first autosomal recessive locus (DFNB1) was mapped few years later [5], and pathogenic variants in GJB2 gene encoding Connexin 26 were identified in 1997 [6]. However, due to the extreme genetic heterogeneity of non-syndromic hearing loss, the research in this field radically changed only after the advent of next-generation sequencing technologies.

In this Special Issue, we would like to collect contributions on the genetics of hearing loss, a continuously evolving topic. 

Reference

[1] Nance, W.E. Genetic Counseling for the Hearing Impaired. Int. J. Audiol. 1971, 10, 222–233, doi: 10.3109/00206097109072563.

[2] Konigsmark, B.W.; Gorlin, R.J. Genetic and Metabolic Deafness; W B Saunders Co: Philadelphia, PA, USA, 1976.

[3] Brunner, H.G.; van Bennekom, A.; Lambermon, E.M.; Oei, T.L.; Cremers, W.R.; Wieringa, B.; Ropers, H.H. The gene for X-linked progressive mixed deafness with perilymphatic gusher during stapes surgery (DFN3) is linked to PGK. Hum. Genet. 1988, 80, 337–340, doi: 10.1007/BF00273647.

[4] Wallis, C.; Ballo, R.; Wallis, G.; Beighton, P.; Goldblatt, J. X-linked mixed deafness with stapes fixation in a Mauritian kindred: linkage to Xq probe pDP34. Genomics. 1988, 3, 299–301, doi: 10.1016/0888-7543(88)90119-x.

[5] Guilford, P.; Ben Arab, S.; Blanchard, S.; Levilliers, J.; Weissenbach, J.; Belkahia, A.; Petit, C. A non-syndrome form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat. Genet. 1994, 6, 24–28. doi: 10.1038/ng0194-24.

[6] Kelsell, D.P.; Dunlop, J.; Stevens, H.P.; Lench, N.J.; Liang, J.N.; Parry, G.; Mueller, R.F.; Leigh, I.M. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997, 387, 80–83. doi: 10.1038/387080a0.

Thank you very much!

Prof. Dr. Alessandro Martini
Prof. Dr. Matteo Cassina
Guest Editors

Manuscript Submission Information

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Keywords

  • hearing loss
  • deafness
  • genetics
  • hereditary
  • next generation sequencing

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Published Papers (11 papers)

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Editorial

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3 pages, 1154 KiB  
Editorial
Victor A. McKusick, the “Father of Medical Genetics”
by Alessandro Martini and Matteo Cassina
Audiol. Res. 2021, 11(4), 636-638; https://doi.org/10.3390/audiolres11040058 - 25 Nov 2021
Cited by 1 | Viewed by 2334 | Correction
Abstract
The Special Issue “Genetics of hearing loss” is dedicated to Victor A [...] Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
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Research

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12 pages, 1795 KiB  
Article
Genetic and Non Genetic Hearing Loss and Associated Disabilities: An Epidemiological Survey in Emilia-Romagna Region
by Elisabetta Genovese, Silvia Palma, Valeria Polizzi, Giovanni Bianchin, Michela Cappai, Shaniko Kaleci, Alessandro Martini, Andrea Ciorba and Paolo Stagi
Audiol. Res. 2021, 11(3), 463-473; https://doi.org/10.3390/audiolres11030043 - 16 Sep 2021
Viewed by 3136
Abstract
Hearing loss is one of the most common congenital sensory disorders. It can be associated with several comorbidities, in particular developmental disabilities (DD). In Emilia-Romagna (ER), a region in Northern Italy, Child and Adolescent Mental Health Services (CAMHS) provide the diagnostic framework and [...] Read more.
Hearing loss is one of the most common congenital sensory disorders. It can be associated with several comorbidities, in particular developmental disabilities (DD). In Emilia-Romagna (ER), a region in Northern Italy, Child and Adolescent Mental Health Services (CAMHS) provide the diagnostic framework and treatment for these conditions. The aim of the present study is to evaluate the prevalence of hearing loss, both isolated or in association with comorbidities, in the juvenile population. The study draws its data from the ER Childhood and Adolescent Neuropsychiatry Information System (SINPIAER), an Administrative Healthcare Database collecting the clinical data of all those who have attended CAMHS since 2010. The most frequent type of hearing loss was bilateral sensorineural hearing loss, which was present in 69–72% of the cases, while bilateral conductive hearing loss was the second most common type, ranging from 8 to 10%. Among DD, congenital malformations, mental retardation, visual impairment, and cerebral palsy were the most common. In particular, autism spectrum disorders show increasing incidence and prevalence among CAMHS users in ER region. In-depth knowledge of hearing loss epidemiology and related conditions, such as developmental disabilities, in the juvenile population is crucial for disease prevention, health planning, and resource allocation. Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
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Review

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24 pages, 1844 KiB  
Review
Usher Syndrome
by Alessandro Castiglione and Claes Möller
Audiol. Res. 2022, 12(1), 42-65; https://doi.org/10.3390/audiolres12010005 - 11 Jan 2022
Cited by 30 | Viewed by 10608
Abstract
Usher syndrome (USH) is the most common genetic condition responsible for combined loss of hearing and vision. Balance disorders and bilateral vestibular areflexia are also observed in some cases. The syndrome was first described by Albrecht von Graefe in 1858, but later named [...] Read more.
Usher syndrome (USH) is the most common genetic condition responsible for combined loss of hearing and vision. Balance disorders and bilateral vestibular areflexia are also observed in some cases. The syndrome was first described by Albrecht von Graefe in 1858, but later named by Charles Usher, who presented a large number of cases with hearing loss and retinopathy in 1914. USH has been grouped into three main clinical types: 1, 2, and 3, which are caused by mutations in different genes and are further divided into different subtypes. To date, nine causative genes have been identified and confirmed as responsible for the syndrome when mutated: MYO7A, USH1C, CDH23, PCDH15, and USH1G (SANS) for Usher type 1; USH2A, ADGRV1, and WHRN for Usher type 2; CLRN1 for Usher type 3. USH is inherited in an autosomal recessive pattern. Digenic, bi-allelic, and polygenic forms have also been reported, in addition to dominant or nonsyndromic forms of genetic mutations. This narrative review reports the causative forms, diagnosis, prognosis, epidemiology, rehabilitation, research, and new treatments of USH. Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
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14 pages, 2491 KiB  
Review
Electrocochleography in Auditory Neuropathy Related to Mutations in the OTOF or OPA1 Gene
by Rosamaria Santarelli, Pietro Scimemi, Chiara La Morgia, Elona Cama, Ignacio del Castillo and Valerio Carelli
Audiol. Res. 2021, 11(4), 639-652; https://doi.org/10.3390/audiolres11040059 - 26 Nov 2021
Cited by 2 | Viewed by 4244
Abstract
Auditory Neuropathy (AN) is characterized by disruption of temporal coding of acoustic signals in auditory nerve fibers resulting in alterations of auditory perceptions. Mutations in several genes have been associated to the most forms of AN. Underlying mechanisms include both pre-synaptic and post-synaptic [...] Read more.
Auditory Neuropathy (AN) is characterized by disruption of temporal coding of acoustic signals in auditory nerve fibers resulting in alterations of auditory perceptions. Mutations in several genes have been associated to the most forms of AN. Underlying mechanisms include both pre-synaptic and post-synaptic damage involving inner hair cell (IHC) depolarization, neurotransmitter release, spike initiation in auditory nerve terminals, loss of auditory fibers and impaired conduction. In contrast, outer hair cell (OHC) activities (otoacoustic emissions [OAEs] and cochlear microphonic [CM]) are normal. Disordered synchrony of auditory nerve activity has been suggested as the basis of both the alterations of auditory brainstem responses (ABRs) and reduction of speech perception. We will review how electrocochleography (ECochG) recordings provide detailed information to help objectively define the sites of auditory neural dysfunction and their effect on receptor summating potential (SP) and neural compound action potential (CAP), the latter reflecting disorders of ribbon synapses and auditory nerve fibers. Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
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13 pages, 2557 KiB  
Review
Genetics of Inner Ear Malformations: A Review
by Davide Brotto, Flavia Sorrentino, Roberta Cenedese, Irene Avato, Roberto Bovo, Patrizia Trevisi and Renzo Manara
Audiol. Res. 2021, 11(4), 524-536; https://doi.org/10.3390/audiolres11040047 - 12 Oct 2021
Cited by 8 | Viewed by 4866
Abstract
Inner ear malformations are present in 20% of patients with sensorineural hearing loss. Although the first descriptions date to the 18th century, in recent years the knowledge about these conditions has experienced terrific improvement. Currently, most of these conditions have a rehabilitative option. [...] Read more.
Inner ear malformations are present in 20% of patients with sensorineural hearing loss. Although the first descriptions date to the 18th century, in recent years the knowledge about these conditions has experienced terrific improvement. Currently, most of these conditions have a rehabilitative option. Much less is known about the etiology of these anomalies. In particular, the evolution of genetics has provided new data about the possible relationship between inner ear malformations and genetic anomalies. In addition, in syndromic condition, the well-known presence of sensorineural hearing loss can now be attributed to the presence of an inner ear anomaly. In some cases, the presence of these abnormalities should be considered as a characteristic feature of the syndrome. The present paper aims to summarize the available knowledge about the possible relationships between inner ear malformations and genetic mutations. Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
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20 pages, 5938 KiB  
Review
Genetic Determinants of Non-Syndromic Enlarged Vestibular Aqueduct: A Review
by Sebastian Roesch, Gerd Rasp, Antonio Sarikas and Silvia Dossena
Audiol. Res. 2021, 11(3), 423-442; https://doi.org/10.3390/audiolres11030040 - 28 Aug 2021
Cited by 20 | Viewed by 7107
Abstract
Hearing loss is the most common sensorial deficit in humans and one of the most common birth defects. In developed countries, at least 60% of cases of hearing loss are of genetic origin and may arise from pathogenic sequence alterations in one of [...] Read more.
Hearing loss is the most common sensorial deficit in humans and one of the most common birth defects. In developed countries, at least 60% of cases of hearing loss are of genetic origin and may arise from pathogenic sequence alterations in one of more than 300 genes known to be involved in the hearing function. Hearing loss of genetic origin is frequently associated with inner ear malformations; of these, the most commonly detected is the enlarged vestibular aqueduct (EVA). EVA may be associated to other cochleovestibular malformations, such as cochlear incomplete partitions, and can be found in syndromic as well as non-syndromic forms of hearing loss. Genes that have been linked to non-syndromic EVA are SLC26A4, GJB2, FOXI1, KCNJ10, and POU3F4. SLC26A4 and FOXI1 are also involved in determining syndromic forms of hearing loss with EVA, which are Pendred syndrome and distal renal tubular acidosis with deafness, respectively. In Caucasian cohorts, approximately 50% of cases of non-syndromic EVA are linked to SLC26A4 and a large fraction of patients remain undiagnosed, thus providing a strong imperative to further explore the etiology of this condition. Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
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Other

1 pages, 156 KiB  
Correction
Correction: Martini, A.; Cassina, M. Victor A. McKusick, the “Father of Medical Genetics”. Audiol. Res. 2021, 11, 636–638
by Alessandro Martini and Matteo Cassina
Audiol. Res. 2022, 12(1), 95; https://doi.org/10.3390/audiolres12010011 - 17 Feb 2022
Viewed by 1672
Abstract
In the original article [...] Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
7 pages, 234 KiB  
Commentary
Genetics & Epigenetics of Hereditary Deafness: An Historical Overview
by Alessandro Martini, Flavia Sorrentino, Ugo Sorrentino and Matteo Cassina
Audiol. Res. 2021, 11(4), 629-635; https://doi.org/10.3390/audiolres11040057 - 17 Nov 2021
Cited by 3 | Viewed by 3282
Abstract
Hearing loss (HL) is one of the most common sensory impairments worldwide and represents a critical medical and public health issue. Since the mid-1900s, great efforts have been aimed at understanding the etiology of both syndromic and non-syndromic HL and identifying correlations with [...] Read more.
Hearing loss (HL) is one of the most common sensory impairments worldwide and represents a critical medical and public health issue. Since the mid-1900s, great efforts have been aimed at understanding the etiology of both syndromic and non-syndromic HL and identifying correlations with specific audiological phenotypes. The extraordinary discoveries in the field of molecular genetics during the last three decades have contributed substantially to the current knowledge. Next-generation sequencing technologies have dramatically increased the diagnostic rate for genetic HL, enabling the detection of novel variants in known deafness-related genes and the discovery of new genes implicated in hearing disease. Overall, genetic factors account for at least 40% of the cases with HL, but a portion of affected patients still lack a definite molecular diagnosis. Important steps forward have been made, but many aspects still have to be clarified. In particular, the role of epigenetics in the development, function and pathology of hearing is a research field that still needs to be explored. This research is extremely challenging due to the time- and tissue-dependent variability of the epigenetic changes. Multisystem diseases are expected to be investigated at first: specific epi-signatures have been identified for several syndromic disorders and represent potential markers for molecular diagnostics. Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
9 pages, 974 KiB  
Case Report
A Rare Case of Perrault Syndrome with Auditory Neuropathy Spectrum Disorder: Cochlear Implantation Treatment and Literature Review
by Francesca Forli, Luca Bruschini, Beatrice Franciosi, Roberta Battini, Gemma Marinella, Stefano Berrettini and Francesco Lazzerini
Audiol. Res. 2021, 11(4), 609-617; https://doi.org/10.3390/audiolres11040055 - 13 Nov 2021
Cited by 5 | Viewed by 2983
Abstract
Perrault syndrome (PRLTS) is a rare autosomal recessive disorder characterised by ovarian failure in females and sensorineural hearing loss (SNHL) in both genders. In the present paper we describe a child affected by PRLTS3, due to CLPP homozygous mutations, presenting auditory neuropathy spectrum [...] Read more.
Perrault syndrome (PRLTS) is a rare autosomal recessive disorder characterised by ovarian failure in females and sensorineural hearing loss (SNHL) in both genders. In the present paper we describe a child affected by PRLTS3, due to CLPP homozygous mutations, presenting auditory neuropathy spectrum disorder (ANSD) with bilateral progressive SNHL. This is the first case reported in the literature of an ANSD in PRLTS3. CLPP is a nuclear encoded mitochondrial protease directed at the mitochondrial matrix. It is encoded on chromosome 19. This protease participates in mitochondrial protein quality control by degrading misfolded or damaged proteins, thus maintaining the normal metabolic function of the cell. In PRLTS3, the peptidase activity of CLPP is suppressed. Neurological impairments involved in PRLTS3 suggest that the pathogenic mutations in CLPP might trigger a mitochondrial dysfunction. A comprehensive description of the clinical and audiological presentation, as well as the issues related to cochlear implant (CI) procedure and the results, are addressed and discussed. A brief review of the literature on this topic is also provided. Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
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12 pages, 590 KiB  
Case Report
DFNA20/26 and Other ACTG1-Associated Phenotypes: A Case Report and Review of the Literature
by Ugo Sorrentino, Chiara Piccolo, Chiara Rigon, Valeria Brasson, Eva Trevisson, Francesca Boaretto, Alessandro Martini and Matteo Cassina
Audiol. Res. 2021, 11(4), 582-593; https://doi.org/10.3390/audiolres11040052 - 18 Oct 2021
Cited by 6 | Viewed by 3093
Abstract
Since the early 2000s, an ever-increasing subset of missense pathogenic variants in the ACTG1 gene has been associated with an autosomal-dominant, progressive, typically post-lingual non-syndromic hearing loss (NSHL) condition designed as DFNA20/26. ACTG1 gene encodes gamma actin, the predominant actin protein in the [...] Read more.
Since the early 2000s, an ever-increasing subset of missense pathogenic variants in the ACTG1 gene has been associated with an autosomal-dominant, progressive, typically post-lingual non-syndromic hearing loss (NSHL) condition designed as DFNA20/26. ACTG1 gene encodes gamma actin, the predominant actin protein in the cytoskeleton of auditory hair cells; its normal expression and function are essential for the stereocilia maintenance. Different gain-of-function pathogenic variants of ACTG1 have been associated with two major phenotypes: DFNA20/26 and Baraitser–Winter syndrome, a multiple congenital anomaly disorder. Here, we report a novel ACTG1 variant [c.625G>A (p. Val209Met)] in an adult patient with moderate-severe NSHL characterized by a downsloping audiogram. The patient, who had a clinical history of slowly progressive NSHL and tinnitus, was referred to our laboratory for the analysis of a large panel of NSHL-associated genes by next generation sequencing. An extensive review of previously reported ACTG1 variants and their associated phenotypes was also performed. Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
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10 pages, 1429 KiB  
Case Report
Compound Heterozygosity for OTOA Truncating Variant and Genomic Rearrangement Cause Autosomal Recessive Sensorineural Hearing Loss in an Italian Family
by Rocco Pio Ortore, Maria Pia Leone, Orazio Palumbo, Antonio Petracca, Eleonora M. C. Trecca, Aurelio D’Ecclesia, Ciro Lucio Vigliaroli, Lucia Micale, Francesco Longo, Salvatore Melchionda and Marco Castori
Audiol. Res. 2021, 11(3), 443-451; https://doi.org/10.3390/audiolres11030041 - 9 Sep 2021
Cited by 1 | Viewed by 2776
Abstract
Hearing loss (HL) affects 1–3 newborns per 1000 and, in industrialized countries, recognizes a genetic etiology in more than 80% of the congenital cases. Excluding GJB2 and GJB6, OTOA is one of the leading genes associated with autosomal recessive non-syndromic HL. Allelic [...] Read more.
Hearing loss (HL) affects 1–3 newborns per 1000 and, in industrialized countries, recognizes a genetic etiology in more than 80% of the congenital cases. Excluding GJB2 and GJB6, OTOA is one of the leading genes associated with autosomal recessive non-syndromic HL. Allelic heterogeneity linked to OTOA also includes genomic rearrangements facilitated by non-allelic homologous recombination with the neighboring OTOAP1 pseudogene. We present a couple of Italian siblings affected by moderate to severe sensorineural hearing loss (SNHL) due to compound heterozygosity at the OTOA locus. Multigene panel next-generation sequencing identified the c.2223G>A, p.(Trp741*) variant transmitted from the unaffected mother. Assuming the existence of a second paternal deleterious variant which evaded detection at sequencing, genomic array analysis found a ~150 Kb microdeletion of paternal origin and spanning part of OTOA. Both deleterious alleles were identified for the first time. This study demonstrates the utility of an integrated approach to solve complex cases and allow appropriate management to affected individuals and at-risk relatives. Full article
(This article belongs to the Special Issue Genetics of Hearing Loss)
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