Information on the genetic basis of and testing for disorders with hearing loss is increasing rapidly. In this review, the authors explain genetic terminology, the principles of inheritance, and the types of genetic variation and the genetic basis of selected disorders of hearing loss. The authors also review how information on genetics and genetic testing can be obtained, outline a genetic approach to the diagnosis of hearing loss, and discuss how otologists and geneticists can work together to strengthen the clinical applications of genetics to individuals and families who have hearing loss.
- 1.
Information on the genetic basis of and testing for disorders with hearing loss is increasing rapidly.
- 2.
Otologists, genetics professionals, and specialized laboratory testing are needed for the diagnosis, education, counseling, and management of patients and families with familial hearing loss.
- 3.
A variety of electronic databases can provide rapid access to information needed on genetic causes of hearing loss.
- 4.
The genetic approach to the evaluation of hearing loss requires otologic, audiologic, and physical examinations; the use of family history; and ancillary and molecular genetic testing.
The genetics revolution
The Human Genome Project has provided a wealth of information on the sequence and organization of the human genome, which is the genetic equivalent of the Rosetta stone. This data has enabled scientists to decipher the code of the estimated 20,000 genes contained in the approximately 3.3 billion bases of the human genome. In addition, comparisons of the genomes of different normal individuals have shown that about 1 out of 1300 bases differ at a frequency of 1% or more. These frequent variations are referred to as polymorphisms. Thus, every gene is likely to contain polymorphisms, which may be functionally important. In addition, rarer variations that occur in less than 1% of people can be identified, which, either alone or in combination with environmental factors, can cause human genetic diseases.
New findings on the genetic basis of hearing loss are reported at an ever-increasing rate in a growing variety of books, journals, and databases. Unfortunately, up-to-date information on clinical and laboratory findings of disorders causing hearing loss and the accuracy and availability of genetic tests cannot be found in a single source. Electronic databases can provide medical professionals rapid access to current clinical and genetic information. These electronic databases can be searched interactively for specific symptoms and signs to produce a list of differential diagnoses and access corresponding genetic tests. The use of these databases should improve the ability of otologists to identify rare or recently discovered genetic causes of hearing loss and the subtleties that differentiate the various alternative diagnoses.
Identifying the genetic basis of hearing loss is becoming more useful. For example, newborn screening and molecular testing for hearing loss have enhanced detection and improved the outcome of infants with congenital hearing loss. In this article, the authors review the principles of inheritance, genetic terminology, types of mutations, outline a genetic approach to the diagnosis of hearing loss, show how information on genetic disorders and testing can be obtained, and outline how otologists and geneticists can work together to strengthen the clinical applications of genetics to hearing loss.
Genetic terminology, genetic variations, effects of variations on gene function, and forms of inheritance
Selected Genetic Terms
Alleles are versions of a gene that occur at a single locus. When a person has a pair of identical alleles, they are homozygous (a homozygote) and when the alleles are different, they are heterozygous (a heterozygote or carrier). A compound heterozygote is a genotype in which two different mutant alleles of the same gene are present. The terms homozygous, heterozygous, and compound heterozygous can refer to either a person or a genotype.
Expressivity is the severity of expression of the phenotype or the extent to which a genetic defect is expressed. When the severity of disease differs in those who have the same genotype, the phenotype has variable expressivity.
Genotype is the set of different versions of the gene (alleles) that occur at a given locus.
Heterogeneity is explained as follows: Genetic disorders often include several phenotypes that are similar but are actually determined by different genotypes. Genetic heterogeneity can result from different mutations at the same locus (allelic heterogeneity), mutations at different loci (locus heterogeneity), or both. Recognition of genetic heterogeneity is important in clinical diagnosis, prognosis, and genetic counseling regarding recurrence risks. Phenotypic heterogeneity occurs when clinically different phenotypes are caused by different mutations in the same gene.
Imprinting is the process by which certain genes or chromosomal regions are modified during meiosis so that gene expression varies depending on parental origin.
Locus is the position occupied by a gene on a chromosome. Different forms of the gene (alleles) can occupy a locus.
Mutation is used in medical genetics in two ways:
- 1.
To indicate a new genetic change that has not been previously known in a kindred
- 2.
To indicate a disease-causing allele
Penetrance is the fraction of individuals with a disease-causing genotype that has any signs or symptoms of the disease. When the frequency of expression of a phenotype is less than 100% (eg, some of those who have the appropriate genotype completely fail to express it), the gene is said to show reduced penetrance. Penetrance is an all-or-none concept.
Phenotype is the observed morphologic, clinical, cellular, or biochemical characteristics determined by genotype and environment (ie, phenotype = genotype + environment).
Pleiotropy means there are multiple phenotypic effects of a single gene or gene pair. Pleiotropy is most often used when the effects are not obviously related.
Uniparental disomy (UPD) occurs when both members of a chromosome pair are inherited from one parent and neither chromosome is inherited from the other parent.
Genetic Variations
Frameshift mutations are insertions or deletions of several codon bases that are not multiples of 3. Such changes disrupt the codon reading frame and usually cause the creation of a premature termination (or stop) codon that ends translation of the encoded protein.
Missense mutations are single base pair substitutions that result in the translation of a different amino acid for the altered codon (unit of 3 bases).
Nonsense mutations introduce a premature termination (or stop) codon that encodes a truncated protein product.
Polymorphism is the occurrence in a population of two or more alleles, each at a frequency of at least 1%. Alleles with a lower frequency than 1% are often referred to as rare variants.
Effects of Variations on Gene Function
In autosomal dominant (AD) disorders, disease occurs despite the presence of a normal gene or allele. There are at least four mechanisms that allow the mutant AD allele to overpower the remaining normal allele and cause AD disorders :
Dominant negative is explained as follows: Instead of a simple deficiency or dysfunction of the protein product, an abnormal protein is synthesized that causes an abnormal phenotype by interfering with the function of the product of the normal allele (dominant negative effect) as is seen in DFNA2A (Online Mendelian Inheritance in Man [OMIM] # 600101) and DFNA9 (OMIM # 601369).
Gain of function occurs when the mutant protein can gain properties through mutation (simple gain of function) or become toxic to the cell through acquisition of a novel property as in some forms of DFNA5 (OMIM # 600994).
Haploinsufficiency occurs when the contribution of a normal allele is insufficient to prevent disease, because of a loss-of-function mutation of the other allele. A phenotype occurs in heterozygotes despite one of the pair of alleles being fully functional because loss of half of the normal activity of two genes causes disease. Haploinsufficiency often occurs with mutations in genes encoding transcription factors, structural proteins, or cell surface receptors. An example is DFNA2A (OMIM # 600101).
Two-hit mutation is an inherited mutation of one copy of some autosomal genes (first hit or mutation). For example, mutations in the neurofibromatosis type 2 (NF2) gene can result in pedigrees with dominantly inherited tumors, such as acoustic neuromas in NF2 (OMIM # 101000). Random loss of the other normal allele caused by a rare event occurring in a somatic cell (second hit or mutation) eliminates both copies of the gene in such cells and renders them cancerous. Thus, although the predisposition to tumors in NF2 is inherited as an AD trait, the mutations that lead to cancer are recessive at the cellular level because both copies of the gene must be dysfunctional for this type of cancer to develop.
Forms of Inheritance
Mendelian inheritance
AD inheritance describes a trait or disorder in which the phenotype is expressed in those who have inherited only one copy or allele of a particular gene mutation along with a normal allele. These individuals are referred to as heterozygotes. The term autosomal indicates that the gene resides on one of the 22 pairs of autosomes, which are the non-sex chromosomes. AD disorders are inherited equally by males and females. Offspring of a heterozygous parent have a 50% chance of inheriting the mutation. De novo mutations are those mutations that occur for the first time in the index case. Factors, such as de novo mutations, mosaicism, penetrance, and variable expressivity, can contribute to differences in the recurrence risk or clinical severity of AD disorders.
Autosomal recessive (AR) inheritance describes a trait or disorder in which the phenotype is only expressed in those who have two copies (alleles) of a gene that is mutated at a particular autosomal locus. These individuals are referred to as homozygotes if the mutations in their two alleles are identical and as “compound heterozygotes” if their alleles differ. Carriers are persons who have one mutant allele and one normal allele and who typically do not express the disease phenotype. Unaffected parents of a child with an AR disorder are obligate carriers who have a 25% recurrence risk as a couple. The term consanguinity is used to describe couples who are genetically related and, therefore, more likely to share alleles that cause autosomal recessive disorders.
X-linked dominant (XLD) inheritance describes a dominant trait or disorder in which the phenotype is caused by a mutation in a gene on the X chromosome. Although the phenotype is seen in both females (who are heterozygous) and males (who have only one X chromosome and are, thus, hemizygous), males tend to be more severely affected. Offspring of affected heterozygous females have a 50% risk to inherit the mutation. All of the daughters and none of the sons of affected males inherit the mutation.
X-linked recessive inheritance also describes a trait or disorder in which the phenotype is caused by a mutation in a gene on the X chromosome. It differs from XLD in that the phenotype is seen only in hemizygous males and homozygous females. Although carrier females who have only one copy of the mutation do not usually express the phenotype, some may be affected because of non-random X-chromosome inactivation or, rarely, X-chromosome inactivation as a result of chromosomal translocation involving the healthy allele. Offspring of carrier females have a 50% risk to inherit the mutation and all daughters of affected males are obligate carriers.
Causes of Nonmendelian Inheritance
Imprinting is the process whereby certain genes or chromosomal regions are modified during meiosis so that gene expression varies depending on parental origin. For example, some genes are only expressed if paternally inherited, such as familial paragangliomas with sensorineural hearing loss (OMIM # 168000), whereas others must be maternally inherited to be expressed. Nonmendelian inheritance of a disease can occur if an individual inherits imprinted gene alleles from only one parent such that both copies are silenced.
UPD occurs when both members of a chromosome pair are inherited from one parent and neither is inherited from the other parent. An abnormal phenotype and nonmendelian disease expression can occur if the chromosomal region involved includes imprinted genes. For example, one form of retinitis pigmentosa can be caused by uniparental paternal disomy of the USH2A gene (OMIM # 608400).
Mitochondrial (MT) inheritance describes a trait or disease that is transmitted through the separate genome of the mitochondria, which are cytoplasmic organelles. Mutations in genes, such as MTRNR1, that cause aminoglycoside-induced deafness (OMIM # 580000) are always maternally inherited because ova contain mitochondria, whereas sperm do not. Related terms include homoplasmy (all mitochondria in a cell have the mutation) or heteroplasmy (some mitochondria have the mutation and some do not).
Genetic terminology, genetic variations, effects of variations on gene function, and forms of inheritance
Selected Genetic Terms
Alleles are versions of a gene that occur at a single locus. When a person has a pair of identical alleles, they are homozygous (a homozygote) and when the alleles are different, they are heterozygous (a heterozygote or carrier). A compound heterozygote is a genotype in which two different mutant alleles of the same gene are present. The terms homozygous, heterozygous, and compound heterozygous can refer to either a person or a genotype.
Expressivity is the severity of expression of the phenotype or the extent to which a genetic defect is expressed. When the severity of disease differs in those who have the same genotype, the phenotype has variable expressivity.
Genotype is the set of different versions of the gene (alleles) that occur at a given locus.
Heterogeneity is explained as follows: Genetic disorders often include several phenotypes that are similar but are actually determined by different genotypes. Genetic heterogeneity can result from different mutations at the same locus (allelic heterogeneity), mutations at different loci (locus heterogeneity), or both. Recognition of genetic heterogeneity is important in clinical diagnosis, prognosis, and genetic counseling regarding recurrence risks. Phenotypic heterogeneity occurs when clinically different phenotypes are caused by different mutations in the same gene.
Imprinting is the process by which certain genes or chromosomal regions are modified during meiosis so that gene expression varies depending on parental origin.
Locus is the position occupied by a gene on a chromosome. Different forms of the gene (alleles) can occupy a locus.
Mutation is used in medical genetics in two ways:
- 1.
To indicate a new genetic change that has not been previously known in a kindred
- 2.
To indicate a disease-causing allele
Penetrance is the fraction of individuals with a disease-causing genotype that has any signs or symptoms of the disease. When the frequency of expression of a phenotype is less than 100% (eg, some of those who have the appropriate genotype completely fail to express it), the gene is said to show reduced penetrance. Penetrance is an all-or-none concept.
Phenotype is the observed morphologic, clinical, cellular, or biochemical characteristics determined by genotype and environment (ie, phenotype = genotype + environment).
Pleiotropy means there are multiple phenotypic effects of a single gene or gene pair. Pleiotropy is most often used when the effects are not obviously related.
Uniparental disomy (UPD) occurs when both members of a chromosome pair are inherited from one parent and neither chromosome is inherited from the other parent.
Genetic Variations
Frameshift mutations are insertions or deletions of several codon bases that are not multiples of 3. Such changes disrupt the codon reading frame and usually cause the creation of a premature termination (or stop) codon that ends translation of the encoded protein.
Missense mutations are single base pair substitutions that result in the translation of a different amino acid for the altered codon (unit of 3 bases).
Nonsense mutations introduce a premature termination (or stop) codon that encodes a truncated protein product.
Polymorphism is the occurrence in a population of two or more alleles, each at a frequency of at least 1%. Alleles with a lower frequency than 1% are often referred to as rare variants.
Effects of Variations on Gene Function
In autosomal dominant (AD) disorders, disease occurs despite the presence of a normal gene or allele. There are at least four mechanisms that allow the mutant AD allele to overpower the remaining normal allele and cause AD disorders :
Dominant negative is explained as follows: Instead of a simple deficiency or dysfunction of the protein product, an abnormal protein is synthesized that causes an abnormal phenotype by interfering with the function of the product of the normal allele (dominant negative effect) as is seen in DFNA2A (Online Mendelian Inheritance in Man [OMIM] # 600101) and DFNA9 (OMIM # 601369).
Gain of function occurs when the mutant protein can gain properties through mutation (simple gain of function) or become toxic to the cell through acquisition of a novel property as in some forms of DFNA5 (OMIM # 600994).
Haploinsufficiency occurs when the contribution of a normal allele is insufficient to prevent disease, because of a loss-of-function mutation of the other allele. A phenotype occurs in heterozygotes despite one of the pair of alleles being fully functional because loss of half of the normal activity of two genes causes disease. Haploinsufficiency often occurs with mutations in genes encoding transcription factors, structural proteins, or cell surface receptors. An example is DFNA2A (OMIM # 600101).
Two-hit mutation is an inherited mutation of one copy of some autosomal genes (first hit or mutation). For example, mutations in the neurofibromatosis type 2 (NF2) gene can result in pedigrees with dominantly inherited tumors, such as acoustic neuromas in NF2 (OMIM # 101000). Random loss of the other normal allele caused by a rare event occurring in a somatic cell (second hit or mutation) eliminates both copies of the gene in such cells and renders them cancerous. Thus, although the predisposition to tumors in NF2 is inherited as an AD trait, the mutations that lead to cancer are recessive at the cellular level because both copies of the gene must be dysfunctional for this type of cancer to develop.
Forms of Inheritance
Mendelian inheritance
AD inheritance describes a trait or disorder in which the phenotype is expressed in those who have inherited only one copy or allele of a particular gene mutation along with a normal allele. These individuals are referred to as heterozygotes. The term autosomal indicates that the gene resides on one of the 22 pairs of autosomes, which are the non-sex chromosomes. AD disorders are inherited equally by males and females. Offspring of a heterozygous parent have a 50% chance of inheriting the mutation. De novo mutations are those mutations that occur for the first time in the index case. Factors, such as de novo mutations, mosaicism, penetrance, and variable expressivity, can contribute to differences in the recurrence risk or clinical severity of AD disorders.
Autosomal recessive (AR) inheritance describes a trait or disorder in which the phenotype is only expressed in those who have two copies (alleles) of a gene that is mutated at a particular autosomal locus. These individuals are referred to as homozygotes if the mutations in their two alleles are identical and as “compound heterozygotes” if their alleles differ. Carriers are persons who have one mutant allele and one normal allele and who typically do not express the disease phenotype. Unaffected parents of a child with an AR disorder are obligate carriers who have a 25% recurrence risk as a couple. The term consanguinity is used to describe couples who are genetically related and, therefore, more likely to share alleles that cause autosomal recessive disorders.
X-linked dominant (XLD) inheritance describes a dominant trait or disorder in which the phenotype is caused by a mutation in a gene on the X chromosome. Although the phenotype is seen in both females (who are heterozygous) and males (who have only one X chromosome and are, thus, hemizygous), males tend to be more severely affected. Offspring of affected heterozygous females have a 50% risk to inherit the mutation. All of the daughters and none of the sons of affected males inherit the mutation.
X-linked recessive inheritance also describes a trait or disorder in which the phenotype is caused by a mutation in a gene on the X chromosome. It differs from XLD in that the phenotype is seen only in hemizygous males and homozygous females. Although carrier females who have only one copy of the mutation do not usually express the phenotype, some may be affected because of non-random X-chromosome inactivation or, rarely, X-chromosome inactivation as a result of chromosomal translocation involving the healthy allele. Offspring of carrier females have a 50% risk to inherit the mutation and all daughters of affected males are obligate carriers.
Causes of Nonmendelian Inheritance
Imprinting is the process whereby certain genes or chromosomal regions are modified during meiosis so that gene expression varies depending on parental origin. For example, some genes are only expressed if paternally inherited, such as familial paragangliomas with sensorineural hearing loss (OMIM # 168000), whereas others must be maternally inherited to be expressed. Nonmendelian inheritance of a disease can occur if an individual inherits imprinted gene alleles from only one parent such that both copies are silenced.
UPD occurs when both members of a chromosome pair are inherited from one parent and neither is inherited from the other parent. An abnormal phenotype and nonmendelian disease expression can occur if the chromosomal region involved includes imprinted genes. For example, one form of retinitis pigmentosa can be caused by uniparental paternal disomy of the USH2A gene (OMIM # 608400).
Mitochondrial (MT) inheritance describes a trait or disease that is transmitted through the separate genome of the mitochondria, which are cytoplasmic organelles. Mutations in genes, such as MTRNR1, that cause aminoglycoside-induced deafness (OMIM # 580000) are always maternally inherited because ova contain mitochondria, whereas sperm do not. Related terms include homoplasmy (all mitochondria in a cell have the mutation) or heteroplasmy (some mitochondria have the mutation and some do not).
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