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The Genetic Basis of Hearing Loss: Recent Advances and Future Prospects 1Anita Jeyakumar, 2Jennifer Lentz

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The Genetic Basis of Hearing Loss: Recent Advances and Future Prospects 1Anita Jeyakumar, 2Jennifer Lentz IJHNS Anita Jeyakumar, Jennifer Lentz 10.5005/jp-journals-10001-1267 REVIEW ARTICLE The Genetic Basis of Hearing Loss: Recent Advances and Future Prospects 1Anita Jeyakumar, 2Jennifer Lentz ABSTRACT not all HL presents at birth, hearing screening is also Hearing loss (HL) is a common and complex condition that can recommended throughout childhood and adolescence occur at any age, be inherited or acquired, and is associated with a to identify children with later onset HL and allow for wide number of etiologies. HL is the most common sensory deficit early intervention. in newborn children. In developed countries, genetic causes are Approximately 95% of newborns with HL identified considered the most frequent etiology of HL, and are estimated to by newborn hearing screening are born to hearing account for 75% of the causes of HL. Current estimates suggest 3 1% of human genes (200–250 genes) are associated with genetic parents. Analysis of historic data from school age HL, and to date, more than 80 genes with over 1000 mutations children in the United States estimates that up to 60% and 140 loci have been identified associated with non-syndromic of educationally significant congenital HL is caused by HL. The Online Mendelian Inheritance in Man reports more than genetic factors.4 400 syndromes with HL. Syndromic and non-syndromic HL can be caused by different mutations within the same gene. Establishing the genetic cause of HL in prelingual children facilitates the CLASSIFICATION OF HL medical course of action, rehabilitation choices and long term Hearing loss can be classified and described in many care in children. Patients with HL of undiagnosed etiology should be evaluated by a clinical geneticist and consider genetic testing different ways. as a part of their multidisciplinary evaluation. Age of onset: HL is described as congenital, prelingual Keywords: Genetics of hearing loss, Hearing loss, Sensorineural (before the acquisition of speech), postlingual (after the hearing loss. acquisition of speech), adult onset, and presbycusis (age- How to cite this article: Jeyakumar A, Lentz J. The Genetic related late onset HL). Basis of Hearing Loss: Recent Advances and Future Prospects. Type: Sensorineural, conductive, mixed, or auditory Int J Head Neck Surg 2016;7(2):64-71. neuropathy Source of support: Nil Laterality and Symmetry: Unilateral or bilateral; sym- Conflict of interest: None metric or asymmetric Stability: Progressive, nonprogressive, or fluctuating INTRODUCTION Degree of HL: Mild (26–40 dB), moderate (41–55 dB), moderately severe (56–70 dB), severe (71–90 dB), or Hearing loss (HL) is a common and complex condition profound (91 dB or greater) that can occur at any age, be inherited or acquired, and is Configuration of audiogram: Sloping, flat, rising, or mid- associated with a wide number of etiologies. Hearing loss frequency/cookie-bite loss is the most common sensory deficit in newborn children.1 Studies have reported an incidence of 0.2 to 0.3% of HL GENETICS OF HL in the newborn population.1 Early intervention has been proven to be effective in facilitating communication and In developed countries, genetic causes are considered language development in hearing impaired children.2 the most frequent etiology of HL, and are estimated to As a result, newborn hearing screening, which began in account for 75% of the causes of HL.5 Patients with HL of 2001, is mandated throughout the United States. Because undiagnosed etiology should be evaluated by a clinical geneticist.6 An estimated 30% of genetic HL is syndromic 1 2 MD MS FACS, PhD (associated with other findings). Notable syndromes 1 Department of Surgery, Virginia Tech-Carilion Clinic School of like Pendred (enlarged vestibular aqueduct, thyroid Medicine, Roanoke, Virginia, USA problems), Usher (retinitis pigmentosa), Waardenburg 2 Department of Otorhinolaryngology and NeuroScience (pigmentary anomalies), and branchio-oto-renal (BOR, Louisiana State University Health Sciences Center, New Orleans, Los Angeles, USA branchial arch and renal anomalies) syndromes account Corresponding Author: Anita Jeyakumar, MD MS FACS for large percentages of HL in certain populations. Department of Surgery, Division of Otolaryngology, Virginia Syndromic HL can be transmitted in an autosomal Tech-Carilion Clinic School of Medicine, Roanoke, Virginia, USA recessive, autosomal dominant, X-linked, or mitochondrial Phone: +5405261251, e-mail: [email protected] pattern. Syndromic HL can have variable expression, with 64 IJHNS The Genetic Basis of Hearing Loss: Recent Advances and Future Prospects varying presentations of HL or associated findings. The more than 80 genes with over 1,000 mutations and 140 variations can exist within and between families. loci have been identified associated with nonsyndromic An estimated 70% of genetic HL is nonsyndromic. HL.17 The Online Mendelian Inheritance in Man reports The majority of genetic, nonsyndromic HL is inherited more than 400 syndromes with HL. Syndromic and in an autosomal recessive pattern, and accounts for 75% nonsyndromic HL can be caused by different mutations of hereditary HL.7 The incidence of nonsyndromic HL within the same gene.18 is about 1.33 per 1,000 newborns, but doubles by age The diverse causes of HL, combined with the highly 5 years to 2.7 per 1,000 children.8 Genetic transmission of variable and often overlapping presentations of different nonsyndromic HL can be autosomal dominant (15–25%) forms of HL and expense of genetic testing, challenge or in a minority of cases, X-linked or mitochondrial the ability of traditional clinical evaluations to arrive at (1–2%).9 an etiologic diagnosis for many hearing impaired indi- The DFNB1 locus, which includes the gap junction viduals. Identifying the etiology of HL can affect clinical beta 2 (GJB2) gene (gap junction protein connexin 26) and management, improve prognostic ability, facilitate genetic GJB6 gene (gap junction protein connexin 30), accounts counseling, and enable assessment of the likelihood of for about 50% autosomal recessive nonsyndromic HL and recurrence in relatives of hearing impaired individuals. can account for 15 to 40% of hearing impaired individuals Furthermore, the identification of a previously unrec- in a variety of populations.10 More than 150 HL variants ognized syndrome of HL can be particularly important have been identified in GJB2, but a few mutations account because it allows early management of associated medical for the majority of the GJB2-related HL. Clinically, GJB2- conditions. related HL is sensorineural, usually present at birth, typically bilateral and non-progressive, and can range GENETIC TESTING from mild to profound in severity.11 Data have estimated more than 3 million variants in the Nonsyndromic mitochondrial HL is characterized average human genome.19 Only a small fraction of the by moderate to profound HL and is associated with variants are expected to be functional, and it is unclear mutations in the MT-RNR1 gene (encoding mitochondrial how these genomic variations contribute to the variability 12S ribosomal RNA) or MT-TS1 gene (encoding in human phenotypes.20 In fact, 5 to 10% of the healthy mitochondrial tRNA Ser).12 Mutations in MT-RNR1 population carries a large deletion or duplication > 500 kb are associated with a predisposition to aminoglycoside within their genome.21 toxicity such that even a single dose of aminoglycoside The year 1988 marked the first reported nonsyndromic can lead to bilateral severe to profound HL.13 HL locus mapping to chromosome Xq using a linkage As the population continues to live longer, it is approach.22 This was considered the first step in a estimated that by the year 2020, there will be over 1 billion seven-year process toward identifying the gene POU3F4 people with HL in the world, approximately 10 to 20% of the (a cause of X-linked nonsyndromic HL). Similarly, the world population.14 A majority of the billion are projected first autosomal locus was linked to chromosome 5q31 to have age-related HL. Age-related HL is considered to in 1992, leading to the identification of DIAPH1 (a cause be multifactorial: a combination of undetermined genetic of autosomal dominant nonsyndromic progressive low- susceptibility and environmental influences. Most of the frequency HL) in 1997.23 research on presbycusis has focused on environmental Historically, molecular diagnostic testing for HL etiology. However, more recent literature has discovered used genotyping or deoxyribonucleic acid sequencing several susceptibility loci for presbycusis. Genes that to identify specific HL variants, to screen individual cause increased susceptibility include genes that have genes, or small collections of genes for changes associ- been implicated in other forms of HL like KCNQ4 and ated with HL. The traditional approach was effective in ACTG1 (both can cause nonsyndromic genetic HL), and cases where there was a single gene or a limited number genes involved in oxidative stress like GRM7, GRHL2, of genes that were suspected to be responsible for a type mitochondrial oxidative genes, and glucosaminyl of HL. Examples include the sequencing of the SLC26A4 transferase (N-acetyltransferase).14,15 gene for Pendred syndrome, PAX3 for Waardenburg syn- With certain exceptions, HL progresses with defined drome type 1, MITF and SOX10 for Waardenburg type II, patterns. Autosomal recessive, nonsyndromic HL is and MYO7A and USH2A for Usher syndrome type I generally prelingual, nonprogressive, and severe to and II.24 The traditional screening is cost-effective in a profound. Autosomal dominant, nonsyndromic HL is population where a single gene mutation is responsible generally postlingual and progressive. for a significant percentage of the cases of HL, such as the Current estimates suggest 1% of human genes GJB2 gene in individuals who appear to have autosomal (200–250 genes) are associated with genetic HL.16 To date, recessive nonsyndromic HL. Today, most tests are based International Journal of Head and Neck Surgery, April-June 2016;7(2):64-71 65 Anita Jeyakumar, Jennifer Lentz on next-generation sequencing. These tests use disease- of HL patients.
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