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Hereditary and Congenital Hearing Loss

INTRODUCTION

Genetics has emerged as an important topic in the field of audiology today. It is particularly valuable for the audiologist and health care professional to have a fundamental knowledge of genetics when discussing disorders of the auditory system due to the fact that many conditions have strong genetic associations. Although the purpose of this book is not to provide the reader with a comprehensive coverage of the genetic disorders that can result in hearing loss, we felt that we could not write a book on auditory disorders without dedicating some time to a review of basic genetic principles and disorders. It is beyond the scope of this book to discuss these topics in great depth; however, we provide the reader with some of the more critical concepts associated with genetics, along with a brief overview of the more common genetically based auditory disorders. For those interested in learning more about these topics, the following resources are recommended:

GeneReviews^® (Adam et al., 1993–2019)

Genetics, Embryology, and Development of Auditory and Vestibular Systems (Jones & Jones, 2011)

Genetics Home Reference: Your Guide to Understanding Genetic Conditions (U.S. National Library of Medicine, 2019l)

Hereditary Hearing Loss and Deafness Overview (Shearer, Hildebrand, & Smith, 2017)

Hereditary Hearing Loss and Its Syndromes, Third Edition (Toriello & Smith, 2013)

Hereditary Hearing Loss Homepage (Van Camp & Smith, 2019)

Medical Genetics: Its Applications to Speech, Hearing, and Craniofacial Disorders (Robin, 2008)

GENETICS OVERVIEW

The typical human being has 23 pairs of chromosomes, including 22 pairs of autosomes and a pair of sex chromosomes (i.e., XX in females and XY in males). These chromosomes contain genetic material composed of deoxyribonucleic acid (DNA) that is arranged on chromosomes in units called genes. DNA is inherited from one’s parents and is composed of four chemical bases or nucleotides. A nucleotide is a molecule that consists of a nitrogen-containing base (adenine, guanine, thymine, or cytosine in DNA and adenine, guanine, uracil, or cytosine in RNA), a phosphate group, and a sugar (deoxyribose in DNA and ribose in RNA). These nucleotides are strung together in sequences on strands. There are two strands of DNA nucleotides that bond together to form a double helix. The bond between these two strands is created by the pairing of adenine with thymine and guanine with cytosine.

An important concept when one is discussing monogenic inheritance patterns is that of zygosity, which refers to the similarity of the gene’s two alleles. If the two alleles of a single gene are identical, they are said to be homozygous, whereas if one of the alleles is a wild-type (or normal) allele and the other is mutated, they are referred to as being heterozygous. If both alleles of a gene are affected but by different mutations, then the term compound heterozygous is used. The term hemizygous is used to refer to the condition where only one allele is present, as would be the case in sex-linked genes where only one X chromosome is inherited (e.g., XY).

When an individual is seen for genetic evaluation, a geneticist or genetic counselor will draw a pictorial representation of the family called a pedigree, which includes the history of the family and the occurrence of a specific disorder or syndrome within the family. The individual who first brought the disorder or syndrome to medical attention is called the proband, and this individual is typically indicated in the pedigree by the presence of an arrow. The various symbols used in drawing a pedigree are shown in Figure 9–1, and these will be used in the pedigrees included in this chapter.

Autosomal Recessive Inheritance Pattern

In the autosomal recessive inheritance pattern, both autosomal gene alleles must have a mutation in order for the individual to have the disorder or syndrome. If both parents have an autosomal recessive disorder, then the offspring will inevitably inherit the disorder as the offspring will receive a mutated allele from each parent. However, if both parents are heterozygotes (i.e., they each have one mutated allele and one nonmutated or wild-type allele), the offspring may or may not inherit the disorder depending on the specific allele received from each parent as depicted in Figure 9–2. In the latter scenario, neither parent will manifest the disorder or condition, but both will be carriers of the trait that then can be passed down to their offspring. In such a situation, each parent has a 50% chance of passing a mutated allele to their offspring, and as such, there is a 25% chance of having an offspring with the disorder or syndrome, a 50% chance of having an offspring who does not have the disorder or condition but who would be a carrier (i.e., the offspring would have one mutated allele), and a 25% chance of having an offspring who would neither be a carrier nor have the disorder or syndrome. The same probability exists for every pregnancy and does not change as the number of pregnancies increases. Consanguinity (i.e., parents related by descent) significantly increases the chance that two parents will be carriers for the same mutated recessive gene that they inherited from their common ancestors. Figure 9–3 shows an example of a pedigree that might be observed when there is an autosomal recessive inheritance pattern.

Autosomal Dominant Inheritance Pattern

In the autosomal dominant inheritance pattern, the inheritance of one mutated allele is sufficient to cause a disorder or syndrome (Figure 9–4). With every pregnancy, there is a 50% chance for a parent with a specific disorder or condition to pass the mutated allele to his or her offspring. If the mutated allele is passed to the offspring, he or she will have the same condition or syndrome as the affected parent. Here, unlike in the case of autosomal recessive inheritance, many individuals in different generations of the family may have the disorder or syndrome; however, the severity and the age of onset of the condition may vary among these individuals. This phenomenon is called variable expression and refers to the range in phenotype that a particular genotype might cause (Welch, 2006). A phenotype is the clinical presentation or observable characteristics that result from the expression of a particular genotype (i.e., the constitution of a set of alleles present at one or more sites). For example, the same gene mutation may result in varying degrees of hearing loss within a family, with some individuals having profound hearing loss while others experience milder forms of hearing loss. Another phenomenon that can be associated with autosomal dominant inheritance patterns is reduced penetrance. This refers to the likelihood that a particular genotype will be expressed as a phenotype less than 100% of the time. For example, if 75% of individuals with a particular mutation are deaf and the remainder have normal hearing, this mutation is said to have reduced penetrance. Figure 9–5 provides an example of a pedigree that might be observed when there is an autosomal dominant inheritance pattern.

X-Linked Inheritance Pattern

The X-linked inheritance pattern refers to the mode of transmission of genes on the X chromosome. This is a unique inheritance pattern as females have two X chromosomes (XX), whereas males have one X and one Y chromosome (XY), and most of the X chromosome genes do not have corresponding alleles on the Y chromosome. As a result, if a male has a mutation in a gene on the X chromosome, he will have the condition or disorder associated with that mutation because he only has the one mutated allele. Females, on the other hand, will not typically have the condition or disorder because they have one mutated allele and one wild-type allele. Figure 9–6 shows the inheritance pattern for a recessive X-linked disorder with a maternal carrier. In this inheritance pattern, there is a 25% chance that the couple will have a male offspring with the disorder or syndrome, a 25% chance that the offspring will be an unaffected male, a 25% chance that the offspring will be an unaffected female, and a 25% chance that the offspring will be an unaffected female who is a carrier for the condition. Figure 9–7 depicts a representative pedigree for a family with this type of X-linked recessive trait. The previous discussion addresses the mode of inheritance with a maternal carrier; however, an X-linked recessive disorder or condition can also be inherited paternally. If a male with the disorder or condition mates with a female with two wild-type (normal) alleles, then none of the male offspring will be affected, but all of the females will be carriers who may or may not show milder manifestations of the disorder.

Mitochondrial Inheritance

Although most of the DNA in humans is located in the nucleus, a small amount is located in the energy producing organelles called mitochondria. Humans obtain their mitochondrial DNA from their mothers due to the fact that egg cells contain mitochondria and sperm cells do not. Hence, any mutations in the mtDNA are passed from the mother to all of her children, both males and females. Figure 9–8 provides an example of a pedigree that might be observed when there is a mitochondrial inheritance pattern.

Multifactorial Traits

For many disorders and conditions that result in hearing loss, the cause can be multifactorial (i.e., there can be an intricate interaction between genes and the environment). In these cases, individuals may inherit a predisposition to develop a disorder, but the disorder does not necessarily manifest itself if the individual is not exposed to the environmental conditions that will trigger the response. Genes and environmental factors may also cause a disorder in an additive fashion.

THE GENETICS OF HEARING LOSS

In humans, hearing loss is the most common sensory deficit. The prevalence of congenital hearing loss in newborns is about 2 to 3 per 1,000 (National Institute on Deafness and Other Communication Disorders, 2016). The overall prevalence of hearing loss increases dramatically with age due to the significant increase in the number of individuals with acquired hearing loss in older populations. It is estimated that 1 in 3 people between the ages of 65 and 74 years of age have hearing loss, and nearly half of those over the age of 75 years have hearing loss (National Institute on Deafness and Other Communication Disorders, 2018).

This increase in the prevalence of hearing loss in adults compared to children is due in part to the fact that genetic, medical/health, and environmental factors contribute to the development of hearing loss in many individuals, and in many cases, there are interactions among these factors (e.g., many individuals inherit a gene that increases their susceptibility to the damaging effects of noise exposure). Genetic etiologies account for the majority of hearing losses diagnosed in infancy (often detected by newborn hearing screening) or in very early childhood, with fewer hearing losses in this population attributed to environmental influences such as infections (i.e., cytomegalovirus), prematurity, ototoxicity, and so forth (Kochar, Hildebrand, & Smith, 2007). Genetic etiologies also contribute to a significant proportion of hearing losses of later onset (Kochhar et al., 2007). However, it is difficult to estimate the prevalence of genetic etiologies in age-related hearing loss due to the frequent presence of other comorbidities in older adults and the elderly, coupled with the fact that genetic testing is far less common among older individuals with hearing loss. In a recent publication, Shearer et al. (2017) provided estimates of the percentages of genetic and nongenetically based pediatric hearing losses. These authors estimated that 1 in 500 prelingual children in developed countries have hearing loss, with 80% of these losses being related to genetic causes and the remaining 20% being related to acquired conditions and/or environmental causes. Clearly, genetic etiologies play a major role in congenital hearing loss.

Genetic hearing losses (as well as hearing losses in general) are often classified by type and onset of the hearing loss. These classifications (described in detail in Chapter 3) include the following types of hearing loss: conductive, sensorineural, mixed, and central auditory dysfunction. In addition, the onset of hearing loss is taken into consideration with respect to if the hearing loss develops before the acquisition of speech (prelingual) or after the development of speech and language (postlingual). All congenital hearing losses are prelingual, but not all prelingual hearing losses are congenital. Perhaps the most common and useful classification of hereditary hearing loss is nonsyndromic versus syndromic hearing loss. These types of genetically based hearing losses are discussed in the next section.

Syndromic and Nonsyndromic Hearing Loss

Hearing loss is one of the most common of the sensory disorders, which affects individuals of all ages. As will become evident in the discussion that follows, genetic factors account for the vast majority of congenital hearing losses. Interestingly, even in hearing loss related to aging in the elderly population (i.e., age-related hearing loss), genetics (along with environmental causes in some cases) may play a role in the development of the hearing loss (Alford et al., 2014). In fact, approximately 30 gene mutations have already been associated with age-related hearing loss (Griffith & Friedman, 2017). Genetic hearing losses can be segmented into two main categories: syndromic and nonsyndromic. Syndromic hearing loss involves not only the auditory system but also other systems, making it a multifaceted disorder. Nonsyndromic hearing loss involves primarily the auditory system; however, in some situations, more than the auditory system can be involved but not nearly to the degree as is observed in syndromic hearing loss.

Nonsyndromic Hearing Loss

According to Shearer and colleagues (2017), nonsyndromic hearing losses are much more common in prelingual children than are syndromic hearing losses. They estimate that approximately 80% of the genetic hearing losses in this population is nonsyndromic, with syndromic hearing loss (which will be discussed later) accounting for about 20% of the genetically based hearing losses in prelingual children in developed countries around the world. Nonsyndromic hearing loss can be autosomal dominant or autosomal recessive, with the recessive form accounting for around 80% and the autosomal dominant form accounting for approximately 19% of all nonsyndromic hearing losses. Less than 1% of nonsyndromic hearing losses are reported to have X-linked, mitochondrial, or microRNA (miRNA) forms of inheritance (see Shearer et al., 2017). The miRNA pattern of inheritance, which was not discussed earlier, refers to a small noncoding RNA molecule that functions in RNA degradation or translation repression (Whaid, Shehzad, Khan, & Kim, 2010), and as can be seen in the statistics presented previously, it is an uncommon etiologic basis for genetic hearing loss.

Tables 9–1 and 9–2 provide examples of genes associated with autosomal recessive nonsyndromic hearing loss and autosomal dominant nonsyndromic hearing loss, respectively. Included in each of these tables are the functions associated with each of the genes mentioned. In addition, the typical onset of the hearing loss (i.e., either prelingual or postlingual) associated with these gene mutations is provided for each of the genes listed in both of these tables. These tables provide “examples” of gene mutations that have been associated with a hearing loss, but they are not intended to be exhaustive listings of all genetic mutations that can result in hearing loss. The reader is referred to Shearer et al. (2017) and Van Camp and Smith (2019) for additional information regarding nonsyndromic and syndromic gene mutations related to hearing loss.

Genes create proteins that play a critical role in the development, function, and dysfunction of structures throughout the various systems in the body. There are a variety of genes associated with the auditory system (Hood & Keats, 2011). According to Van Camp and Smith (2019), 75 autosomal recessive genes associated with nonsyndromic hearing loss have been identified. Identifying genes is a challenging process that includes defining the phenotype, finding families that have the genotype of interest, and then pursuing detailed family histories. A few of the better known genes (especially to the audiology and otology communities) are MYO7A, MYO15, and MYH9, which are motor molecules that encode the myosin protein. Also notable are the GJB2, GJB6, and GJB3 genes, which are all categorized as gap junction proteins that encode the proteins connexin 26, 30, and 31, respectively. The myosin genes are associated with movement of actin filaments and the maintenance of the tip-links of hair cells. These “movement” proteins make one think of the motile properties of the outer hair cells and the critical role they play in hearing. The GJB2 gene was one of the first genes identified that was associated with a high percentage of nonsyndromic hearing loss (autosomal recessive). Since the time of this discovery, there have been more than 100 mutations of the GJB2 gene categorized, with these mutations yielding varying degrees of hearing loss (Wingard & Zhao, 2015). Mutations in the connexin 26 gene are one of the major sources of hereditary hearing loss. It was once believed that a disruption in K⁺ recycling was the primary mechanism responsible for hearing loss associated with mutations of this gene; however, this has proven to in fact not be the case (see Wingard & Zhao, 2015). More recently, mouse models have demonstrated that hearing loss associated with connexin deficiencies is not directly related to hair cell degeneration but rather to cochlear developmental disorders (Chen, Chen, Zhu, Liang, & Zhao, 2014). This differs from late-onset hearing loss that is believed to result from a reduction of active cochlear amplification (Zhu et al., 2015). While advances have been made with respect to our knowledge of the genetic mechanisms underlying congenital and late-onset hearing loss, significantly more research in this area is needed.

Mutations of genes such as the ones that have been mentioned previously and/or referred to in the tables can result in hearing loss. Although in some cases certain mutations can result in severe to profound hearing loss, a similar mutation may also result in minimal hearing loss. This kind of variability seems common (Hood & Keats, 2011). Having said this, some trends in regard to hearing loss have been reported. First, a very high percentage of nonsyndromic hearing loss is sensorineural in nature, as the various gene mutations discussed previously affect proteins that influence the structures and functions of the cochlea. There is also some evidence that gene mutations often yield a certain configuration of hearing loss, although the degree of loss may vary. For example, mutations of the GJB2 gene are known to result in a sensorineural hearing loss. Although the degree of the sensorineural loss can vary from mild to profound, there is a trend toward the high frequencies being more involved than the low and middle frequencies in individuals with mutations of this particular gene (Shearer et al., 2017). The earlier discussion has focused on a few of the more common nonsyndromic genes associated with hereditary hearing loss; however, the reader should be aware that there are many other genes that also can result in nonsyndromic hearing loss when genetic mutations of these genes occur. For a more comprehensive listing of these genes, the reader is encouraged to access Shearer et al. (2017).

More than 400 syndromes with associated hearing losses have been identified (see Toriello & Smith, 2013), most of which are rare. These syndromes can be the result of chromosomal anomalies, a single gene mutation, multiple gene mutations, or a combination of genetic and environmental factors. Most of these syndromes are inherited in the autosomal dominant fashion, but some are inherited in autosomal recessive and X-linked transmission patterns (Tables 9–3 and 9–4 provide information on some common syndromes along with their modes of transmission, gene symbols, and clinical findings). As mentioned previously, 20% of the genetically based hearing losses in prelingual children from developed countries around the world are syndromic in nature (see Shearer et al., 2017), and as such, they constitute a much smaller proportion of genetically based hearing losses when compared to nonsyndromic etiologies in this population of children.

Pendred Syndrome. Pendred syndrome is an autosomal recessive disorder with an unknown incidence. In addition to hearing loss, it is typically associated with a thyroid condition called a goiter. Exact prevalence data for Pendred syndrome are unknown; however, it is estimated that it accounts for 7% to 8% of all congenital hearing loss (U.S. National Library of Medicine, 2019e). The hearing loss is sensorineural in nature, and the high frequencies tend to be more involved than the low frequencies. The hearing loss is progressive, bilateral, and often ranging from moderate to profound in severity (Smith, 2017). A characteristic of patients with Pendred syndrome is enlarged vestibular aqueducts, which cause an enlargement of the endolymphatic duct and sac (see the following discussion on vestibular aqueducts). This genetic condition results in a defect in the ion transportation in endolymphatic fluid resorption, and patients also have euthyroid goiter. Pendred syndrome often results from a mutation of the SLC26A4 gene. In addition, the FOXI1 and KCNJ10 genes have also been linked to this syndrome (Smith, 2017).

Usher Syndrome. Individuals with Usher syndrome typically present with sensorineural hearing loss and retinitis pigmentosa. Usher syndrome has been reported to have a prevalence rate of 3 to 6 per 100,000 individuals (Saihan, Webster, Luxon, & Bitner-Glindzicz, 2009). It is believed to account for 50% of the individuals diagnosed with deaf-blindness (Lentz & Keats, 2016a). Several genes have been identified for this syndrome (see Table 9–3). These genes have a role in the structure and function of the cytoskeleton of stereocilia of the hair cells. Mutations in these genes are associated with retinitis pigmentosa (progressive visual loss and blindness), vestibular dysfunction, and ataxia in some cases. Usher syndrome is classified into 3 types, all of which are autosomal recessive.

Type I: Onset of retinitis pigmentosa by 10 years of age. Profound congenital hearing loss and absent vestibular responses are key characteristics. Pathogenic variants in one of six genes (MYO7A, USH1C, CDH23, PCDH15, USH1G, and CIB2) have been associated with this syndrome (Lentz & Keats, 2016a).

Type II: Onset of retinitis pigmentosa in the early 20s. Normal or decreased vestibular function and mild to moderate progressive hearing loss. The hearing loss is characterized by a mild to moderate low-frequency hearing loss and a severe to profound high-frequency hearing loss. Pathogenic variants are found in one of the following three genes: ADGRV1, WHRN (DFNB31), and USH2A (Lentz & Keats, 2016b).

Type IV: Sensorineural hearing loss; pigmentary abnormalities of the skin, hair, and eyes; and Hirschprung disease (an intestinal disorder). Mutations in the EDNRB, EDN3, or SOX10 genes.

Branchiootorenal Spectrum Disorder. Branchiootorenal spectrum disorder (BORSD) syndrome affects about 1 in 40,000 people (Fraser, Sproule, Halel, & Optiz, 1980; National Organization for Rare Disorders, 2018). The term “branchio” in the name of this syndrome is related to the fact that there is maldevelopment of the second branchial arch in patients with this syndrome. The second branchial arch contributes to tissue on the lateral and front of the neck. In order to be classified as having BORSD, an individual must present with one of the following profiles: three major criteria, two major and two minor criteria, or one major criterion and a first degree relative who has been diagnosed with BORSD (Chang et al., 2004). Major criteria include second branchial arch anomalies, deafness, preauricular pits, auricular malformations, and renal anomalies, while minor criteria include anomalies of the external auditory canals, middle ear, and inner ear; preauricular tags; and other features (facial asymmetry, palate abnormalities). In approximately 90% of the cases, the syndrome is passed on from one affected parent to the offspring in an autosomal dominant inheritance pattern. According to Stickens and colleagues (2001), more than 90% of patients with BORSD present with hearing impairment, including mixed, conductive, and sensorineural losses. Hearing loss in affected individuals can range from mild to profound and can be nonprogressive or progressive in nature (Kemperman et al., 2004). Specific abnormalities of the external ear include preauricular pits and tags, lop ear malformations, atresia, or stenosis. There can be middle ear abnormalities that include malformation, dislocations, or fixation of the ossicles, and malformation of the middle ear space. Inner ear anomalies can include cochlear hypoplasia and enlarged cochlear and vestibular aqueducts (Smith, 2018). There are three gene mutations associated with individuals with BORSD including EYA1, SIX1, and SIX5. EYA1 is believed to be the primary gene mutation and is reported to occur in approximately 40% of individuals with BORSD. While both SIX5 and SIX1 have been found to occur in BORSD, they are far less common. In some individuals, a co-existing EYA1 gene mutation has been identified, and it has been hypothesized to be the actual underlying cause of the condition. The proteins produced by these genes play a critical role in embryologic development and mutations that occur are believed to result in abnormal formation of organs and tissues. It should be noted, however, that there are individuals with BORSD who have none of these three gene mutations, which suggests that there is another unidentified gene (or genes) that can result in this particular syndrome (U.S. National Library of Medicine, 2019b).

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