Does my patient have a genetic form of hearing loss?
The answer to this question is "It's very likely."
The majority of hearing loss is caused by mutations ("misspellings") in the DNA (deoxyribonucleic acid) sequence of genes. There are four compounds known as "bases" in a strand of DNA: adenine (A), guanine (G), thymine (T), and cytosine (C). Each DNA molecule consists of two strands that form the shape of a double helix, through the pairing of A with T, and C with G. Thus, knowing the sequence of bases on one DNA strand automatically gives the sequence on the other strand of the double helix.
Humans have approximately 30,000 genes. The DNA sequence of these genes provides the code for producing proteins (which consist of amino acids). Suppose the correct sequence for a short segment of a gene is AGACATTATCTA. Then examples of mutations are:
- AGACATTGTCTA (an A has been replaced by a G at position 8)
- AGAATTATCTA (the C at position 4 has been deleted)
- AGACATGTATCTA (a G has been inserted at position 7)
- AATTATCTA (GAC at positions 2-4 have been deleted)
The presence of a mutation in the DNA sequence means that the code is incorrect, and a non-functioning protein may be produced or that protein may be missing altogether. We now know that mutations in more than 100 genes can cause hearing loss. This is because the proteins formed by these genes are necessary for normal hearing. When they are abnormal or missing, hearing loss results.
How Is Hearing Loss Inherited?
DNA is packaged into chromosomes. They are designated 1-22 (autosomes), X, and Y (sex chromosomes). An offspring inherits one set of chromosomes (amounting to 3 billion base pairs of DNA) from each parent, providing a total of 46 chromosomes [22 autosomal pairs plus XX (female) or XY (male)]. Thus, an offspring inherits two copies of each gene on the autosomes, one from each parent.
By "taking a pedigree," that is, documenting who is affected and who is unaffected in a family, we can determine the most likely pattern of inheritance. (See figure on page 16; circles represent females, squares represent males, and those with hearing loss are filled.) Usually the inheritance pattern for hearing loss is one of four types: autosomal dominant, autosomal recessive, X-linked recessive, or mitochondrial.
Autosomal Dominant: If some family members in each generation are affected, and others are unaffected, then the hearing loss is probably autosomal dominant. Both males and females are equally likely to be affected, and an affected offspring usually has an affected parent. For this type of inheritance pattern, individuals with one normal copy and one abnormal copy (ND) of the gene have hearing loss; those with two normal copies (NN) are unaffected. This means that if one parent is ND and the other is NN, then each of their offspring has a 50% chance of being ND. The figure on page 16 shows an example of a pedigree with autosomal dominant hearing loss.
A disorder that generally follows an autosomal dominant inheritance pattern is Waardenburg syndrome (WS), in which hearing loss is one of several anomalies that may be found in an affected individual (see sidebar). Because expression may be variable, a thorough physical exam and discussion of features in family members is important in order to make sure that a diagnosis of WS is not missed in an individual who presents with hearing loss. For example, a child may have only congenital sensorineural hearing loss, his mother may have normal hearing and very blue eyes, and his grandfather may have had different colored eyes and a white forelock. Having all of this family information suggests that the correct diagnosis for the child is WS, rather than non-syndromic hearing loss.
Autosomal Recessive: The hearing loss is autosomal recessive if only individuals who have two copies of the abnormal gene exhibit hearing loss. Those who have one normal and one abnormal copy are not affected and are called "carriers." But each child of two carrier parents has a 25% chance of inheriting two abnormal copies and thus having hearing loss. Syndromes such as Usher, Pendred, and Jervell & Lange-Nielsen show an autosomal recessive pattern of inheritance.
Family history is quite likely to be negative with an autosomal recessive disorder because an abnormal copy of the gene may be passed on from one (unaffected) carrier to the next for many generations before a couple, who by chance both carry an abnormal copy, has an affected child. In other words, just because nobody else in the family is affected does not mean that the cause is not genetic.
X-linked Recessive: If all the family members with hearing loss are males, and none of the affected fathers have affected sons, then the hearing loss is probably X-linked recessive. This is because males have only one X chromosome and they inherit it from their mother. If the mother is a carrier, each son has a 50% chance of inheriting the abnormal copy of the X-linked gene and having hearing loss. (Note that all daughters of affected fathers will be carriers because they all inherit their father's X chromosome.)
An X-linked form of hearing loss that is of particular concern is one in which the affected boys have profound sensorineural loss as well as a conductive loss resulting from fixation of the stapes foot-plate. However, if stapes surgery is done to try to correct this, a perilymphatic gusher results. Mutations in a gene on the X chromosome, called POU3F4, cause this type of hearing loss. It can be easily diagnosed by examining a CT scan of temporal bones and inner ears. If the CT scan shows that a specific bony defect is present, then surgery to correct the stapes fixation must not be done. Thus, a thorough case history plays an integral role in proper management of this type of hearing loss.
Mitochondrial: Mitochondria are small organelles in our cells that have their own DNA, known as mtDNA. The number of mtDNA base pairs is only about 16,000, but there are many copies of mtDNA in each cell. We inherit all of our mtDNA from our mothers, so if the hearing loss is caused by a mutation in mtDNA, all the children of affected mothers (but none of the children of affected fathers) would be expected to have hearing loss. An mtDNA mutation, in which a G instead of an A is found at position 1555 (called A1555G), causes severe to profound sensorineural hearing loss. However, in some individuals with the A1555G mutation, the hearing loss does not occur until after exposure to aminoglycoside antibiotics. Thus, knowing this mutation is in the family can help to prevent aminoglycoside-induced deafness.
The majority of genetic hearing loss is autosomal recessive, but about 30% is autosomal dominant, and 2%-3% shows an X-linked or mitochondrial pattern of inheritance. Different mutations in the same gene can be associated with both dominant and recessive hearing loss. For example, the most common genetic form of congenital hearing loss is due to mutations in the connexin 26 gene; the majority of these mutations cause recessive hearing loss but a few are dominant.
Also, remember that mutations in many different genes are associated with hearing loss. This means that a child whose parents both have autosomal recessive hearing loss will not necessarily have hearing loss because the parents' hearing loss may be due to mutations in different genes. In this case, each of their children will be carriers of mutations in two different genes, but they will probably have normal hearing.
What Is a Connexin 26 Test?
The possibility that hearing loss may be genetic should be discussed with every patient. I recommend that the majority of patients be encouraged to see a clinical geneticist who will discuss the likely cause of the hearing loss and make sure that the information is understood. The clinical geneticist may suggest genetic diagnostic testing after explaining how this might be helpful; for many patients this is likely to be a connexin 26 test, which is usually done by extracting DNA from a blood sample (or possibly a cheek swab or saliva sample). The diagnostic laboratory sequences the connexin 26 gene in the patient's DNA to determine if there are any mutations. The results are reported to the clinical geneticist who explains the findings to the patient or parents.
Connexin 26 is one of the proteins that is necessary for normal hearing. The most common mutation that is found in the connexin 26 gene in Caucasians is called 35delG, which means that a G is deleted at position 35. The code is read in sets of three bases called "codons," and each codon specifies an amino acid in the protein sequence. Consequently, if one base is missing, the sequence of amino acids is wrong and no functional protein is likely to be produced. The normal and "35delG" (abnormal) sequences from base 22 to base 45 (codons 8 to 13) are:
- Normal: ACG ATC CTG GGG GGT GTG
- "35delG": ACG ATC CTG GGG GTG TGA
The G at position 35 of the normal sequence (underlined and in bold) is missing from the "35delG" sequence, and codons 12 and 13 are quite different in the two sequences. In fact, TGA is a "stop" codon meaning that it signals the end of the protein. Thus, the "35delG" protein would be much shorter (only 12 amino acids) than normal connexin 26 (contains 208 amino acids), and it is unlikely that any protein is formed if the gene contains the 35delG mutation. More than 90 different mutations have been found in the coding sequence of connexin 26. Most are rare, but a few are relatively common in particular populations (e.g., 267delT and 235delC in Ashkenazi Jewish and Asian populations, respectively).
Connexin 26 hearing loss is usually recessive, so affected individuals have a mutation in both copies of their connexin 26 gene. They may have two copies of the same mutation or two different mutations. In either case, one mutation is inherited from the mother and the other from the father.
Unfortunately, the genetic test results are not always straightforward to interpret. For example, sometimes only one mutation is found. There are various possible explanations for this, such as the second mutation was missed, or the individual is a carrier (by chance) and connexin 26 mutations are not the cause of the hearing loss. Also, it is important to understand that failure to detect any mutations in connexin 26 does not mean that the hearing loss is not genetic; many other genes cause hearing loss.
Abnormalities in Other Organs
Most people with hearing loss do not have abnormalities in other organs; they have non-syndromic hearing loss. However, for some people, hearing loss is just one of several problems. A clinical geneticist will perform a thorough physical examination and take a pedigree to obtain health information about other family members in order to determine if a syndrome may be the correct diagnosis.
Examples of associated abnormalities include vision loss due to retinal degeneration (Usher syndrome), enlarged thyroid (Pendred syndrome), and sudden fainting attacks caused by a heart defect (Jervell and Lange-Nielsen syndrome). Unlike WS, which is usually autosomal dominant, these three syndromes all show an autosomal recessive pattern of inheritance. Recognizing that a person with hearing loss may have a syndrome is important from a diagnostic, management, and therapeutic standpoint.
Usher syndrome: More than 3% and perhaps as many as 10% of children with severe to profound sensorineural hearing loss may have Usher syndrome, meaning that they will start to lose their vision in their teenage years. At least 12 different genes are known to cause Usher syndrome, and genetic testing is not usually feasible. However, if the ethnicity of the child with hearing loss is Acadian or Ashkenazi Jewish, then tests for particular mutations in the USH1C gene and the PCDH15 gene, respectively, should be done to rule out these forms of Usher syndrome.
Pendred syndrome: As many as 10% of children with sensorineural hearing loss may have Pendred syndrome. A large vestibular aqueduct and the Mondini deformity are often found, and onset of a goiter occurs around adolescence. Mutations in a gene called SLC26A4 cause Pendred syndrome. More than 60 mutations have been identified and genetic testing is available.
Jervell & Lange-Nielsen syndrome: Although rare, it is crucial to diagnose this syndrome in infants with hearing loss because an associated cardiac abnormality can cause fainting and in some cases, sudden death. Mutations in two genes, KCNQ1 and KCNE1, are known to cause this syndrome. Although genetic testing is feasible, an electrocardiogram provides a quick and accurate diagnosis and is recommended for all children with severe to profound hearing loss. Once diagnosed, treatment with beta-blockers is usually effective.
Future Role of Genetic Tests in Diagnosing Hearing Loss
Genetic testing for many genes associated with hearing loss is likely to become routine within the next 10 years. Knowing the precise cause of the hearing loss will help to determine the most effective management and therapeutic options. In particular, being able to detect Jervell & Lange-Nielsen can prevent a sudden death and diagnosing Usher syndrome a decade or more before the onset of the retinal degeneration will provide time to prepare for or, hopefully within the not too distant future, provide treatment to minimize the vision loss.
At the very least, the rehabilitation specialists will know the diagnosis and be aware that teaching only signed communication to these children may not be the best option, because the onset of their vision loss may detach them from their language community. Tactile methods of signing are available, but they may restrict the patient from community discourse with the large body of ASL users.
The availability of genetic testing is adding a new dimension to our ability to provide the best possible care for individuals with hearing loss. Consider taking a pedigree on your next patient; for detailed instructions, see the Web sites listed on page 17.