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Diseases and Disorders of the Ear |
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Primer on Inherited Deafness
Autosomal and
X-linked Recessive Deafness |
Primer on Inherited Deafness
Disclaimer: This fact sheet is for
education purposes only. Please consult with your doctor or other health
professional to make sure this information applies to your child.
Chances of another Child Having a
hearing loss
If a genetic counselor or family
physician states that a hearing loss in a child is probably genetically based
then the chances are the hearing loss was passed on by an errant gene, and that
there is a high probability that another child will have similar disabilities.
Basic types of genetic (hereditary)-
based deafness
There are a number of different types of
hereditary deafness. It is probably most helpful to divide it into two
categories:
- dominant deafness (autosomal)
- recessive deafness
Autosomal dominant deafness
Autosomal dominant deafness is the
hereditary type of deafness where parents can usually see it being handed on
from one generation to the next.
Fig.1 is an example of a family where
deafness has been inherited with a dominant pattern. Grandparent Jack is
moderately deaf. Of his children, Peter and Sue are moderately deaf, and in the
third generation, Tom and Kerry have moderate deafness. For a deaf person with
dominant deafness there is usually a one-in-two chance he or she will hand this
on to any child. This chance is the same for every pregnancy. Parents with
dominant deafness usually have their children’s hearing tested as young babies.
Then hearing aids can be fitted early if needed and this helps children with
language development. Without the hearing aids a child with deafness may not
learn to speak.
| Fig. 1 - Autosomal
dominant deafness |
 |
Recessive gene-based deafness
In this type of genetic deafness there
may be no family history of deaf relatives and yet one or more children are deaf
for genetic reasons. There are two types of recessive deafness:
- autosomal recessive - affects boys
and girls
- X-linked recessive - affects only
boys
Autosomal recessive deafness
In some families who have a healthy deaf
child they may suspect (but not be able to prove) that the child has an autosomal
recessive form of hearing loss. When deafness appears “out of the blue” and it cannot
be established that there is an external cause, the recurrence risk for a future child to be born deaf
is given as approximately one in six. The lower risk is because occasionally
children are born deaf due to new mutations and also because there may possibly
be unrecognized environmental causes of deafness is some children. Unfortunately, a one-in-six figure is
still quite a high risk, just as high as scoring a six each time you throw a
dice.
Fig. 2 is an example of autosomal
recessive deafness. In this family Terry and Karen have good hearing as does
Terry's brother and Karen's two sisters. However, Craig and June have severe
deafness. Many parents find this surprising, but the explanation is as follows:
| Fig. 2 - Autosomal
recessive deafness |
 |
Autosomes are chromosomes but they are different because they do not
determine a child's sex. There are:
- 22 pairs of autosomes plus two X
chromosomes in female cells, and
- 22 pairs of autosomes and one X and
one Y chromosome in male cells
Genes are arranged on the DNA strands in
an orderly sequence and determine personal
characteristics such as hair color, eye color, height and even whether we get
certain disorders.
A baby starts when an egg cell from the
mother and a sperm cell from the father join together to make an embryo that
grows in the mother's womb. The egg cell contains:
- 22 single autosomes and one X
chromosome (22 auto + X).
The sperm cell contains:
- 22 single autosomes and one X or one
Y chromosome (22 auto + X) or (22 auto + Y).
Adding up the total chromosomes for the
baby makes it either:
- 44 autosomes + X + Y for a male baby
or
- 44 autosomes + two X for a female
baby
It is the father's sperm that determines
the sex of a baby.
Just as chromosomes come in pairs so do
the genes. Each chromosome of a pair has the same gene in the same place. A
dominant gene (H) always has an effect on the child but a recessive gene (h)
only produces its effect if there is no dominant gene to over-ride it. It is
easier to understand if you think of the dominant gene as bigger and louder so
it blocks out the other (recessive) gene from having an effect. Many cases of
deafness are caused by recessive genes. The child inherits one recessive gene
(h) from each parent. Usually the parents have normal hearing as they have one
dominant gene (H) for normal hearing. Each carrier parent has a profile Hh. This
means they carry a bigger gene for hearing and a smaller gene for deafness, so
the strong H (dominant) gene for normal hearing wins and the parent does not
have deafness.
As you can see in Fig. 3 there are four
possible ways in which genes can be handed on to a baby. This couple have a
one-in-four chance of having a deaf child in every pregnancy. When a child is
deaf but otherwise normal and a careful check reveals no other cause, the family
is advised that the deafness could be autosomal recessive in origin.
| Fig. 3 - How
autosomal recessive deafness is transmitted |
 |
X-linked recessive deafness
This type of recessive deafness is very
uncommon and only affects boys. As with hemophilia, the gene for this type of
deafness is on the X chromosome and is passed on to a son by a carrier mother.
One-in-two (half) of her sons will be deaf.
Mitochondrial deafness
This type of deafness also appears to be
very uncommon .Children with this type of deafness often have extra problems
such as in muscle or skin. It is caused by defects in genes in the mitochondria
which are tiny organelles in the cytoplasm (not the nuclei) of human cells which
are responsible for controlling the generation of energy in cells. In children
with mitochondrial gene defects we often see transmission of problems from
mother to all the children, in varying degrees.
Testing for Carrier
Genes
Types of Tests
There are at least 50 different types of deafness
caused by recessive genes.
However, there is one type of autosomal recessive deafness that is much commoner
than the other types. Children with this type of deafness can usually be
identified by a blood test (DNA test) which checks for errors in the connexin 26
gene. This test is available (when indicated) in some Genetics units and
Children’s Hospitals.
Hereditary deafness can be associated
with other birth defects or isolated. Isolated deafness (DFN) is mainly (80%)
due to recessive genes, and at least 20 of these genes have been identified. One
causative gene (GJB2) is mutated in 50% of cases and encodes a gap
junction protein called Connexin 26. Connexins are transmembrane proteins that
form channels that allow rapid transport of small molecules between cells; the
proteins connexin 26 and connexin 30 interact to form a channel
that functions in the inner ear. Testing for connexin 26 gene mutations
can aid in rapid diagnosis of hearing loss. Early diagnosis of hearing defects
can facilitate timely intervention and assist with genetic counseling. The
GJB6 gene is located nearby and encodes connexin 30, a gap junction
protein.
Approximately 15% of deaf persons with only one connexin 26 mutation also
have a 342kb deletion that encompasses connexin 30. In a large North
American population, the overall incidence of GJB2/GJB6 deafness was
2.5%.
The following are the most common tests
that can be performed to get a better idea of what type of genetic deafness you
are dealing with:
-
GJB2 (Connexin 26) Gene Test
Over half of all cases of early childhood
hearing loss are due to genetic causes; mutations in the GJB2 gene,
encoding the connexin 26 protein, represent the largest proportion of these.
As such, all children born with hearing loss, of any severity, are candidates
for connexin 26 gene testing. This is true even if there is no family history
of hearing loss, as this is the most common presentation. This test alone
gives parents the highest likelihood of obtaining a cause for their child's
hearing loss. Furthermore, a positive test result can alleviate anxiety
associated with the worry that other medical problems may arise in their child
due to the association of hearing loss with many other syndromes (e.g. Usher
syndrome in which blindness can develop at a later age).
Epidemiology: 1/2500-1/5000
▪
Both males and females are affected
in equal frequency.
▪
Certain mutations are found with higher frequency in certain
populations (e.g. 35delG in the Caucasian population, 167delT in the
Ashkenazi Jewish population and 235delC in the Asian population).
Clinical
Features:
▪
Nonsyndromic sensorineural hearing loss, typically congenital.
▪
Mild to profound hearing loss (more commonly severe to profound).
▪
Progressive or non-progressive hearing loss.
Inheritance
Pattern: Autosomal recessive.
▪
Typically, each parent is unaffected but is a carrier of a single
mutation in the GJB2 gene.
▪
On average, 25% of the couple's children are expected to inherit both
copies of the mutation and be affected.
Test
Indications:
▪
Congenital/prelingual mild-to-profound sensorineural hearing loss.
Test Purposes
- The identification of the high
frequency of GJB2 gene mutations and the small size of this gene
allows for an excellent diagnostic test.
- All children with bilateral
sensorineural hearing impairment should undergo GJB2 mutation
screening. Cases of unilateral (one-sided) hearing impairment have a very
low chance of testing positive for mutations in the GJB2 gene.
-
Test Outcomes:
▪
The presence of two known pathogenic mutations, one in each copy of
the GJB2 gene, is considered a positive test.
▪
The discovery of one mutation in an affected individual is difficult
to interpret. Some of these individuals may have hearing loss due to another
cause, and be coincidental carriers of the mutation. Others may have a
second mutation that has not been detected by the test. If only one mutation
is found, the patient should have testing for the GJB6 (Connexin 30)
deletion mutation that acts in combination with a single GJB2
mutation to cause hearing loss.
For those patients not having
genetic mutations related to hearing loss, other tests that are considered
include:
- Urinalysis (urine test)
- ECG (for bilateral
severe-profound cases)
- CT scan of the ear bones
Methodology: The first step involves screening for the
35delG mutation. If this screen is negative or heterozygous, exon 1 and the
coding region of exon 2 are amplified using flanking primer sets. PCR
products are sequenced using an ABI fluorescence automatic DNA sequencer.
Analytical and
Clinical Sensitivity:
This assay is greater than 99.9% accurate in detecting mutations in the
sequence analyzed. Two GJB2 mutations are detected in approximately
20% of patients with nonsyndromic sensorineural hearing loss. However, a
negative result does not rule out a diagnosis of GJB2 hearing loss
because there may be other mutations within the GJB2 gene (promoter
or other non-coding or regulatory regions) that are not detected by this
test.
-
GJB6 (Connexin 30) Gene
Test GJB6
deletion testing should be ordered for all patients with one abnormal allele
on GJB2 testing.
-
Pendrin (SLC26A4)
Mutation Testing
PDS Gene Testing for
mutations in the SLC26A4 Gene
Hearing loss caused by mutations in the SLC26A4 gene is most often seen in a person with
one or more of the following symptoms:
-
Temporal bone abnormalities (observed on a CT scan or MRI of the inner
ear)
-
Enlarged (dilated) vestibular aqueduct and/or Mondini
malformation of the inner ear
-
Hearing loss that was found at birth or in early childhood
-
Hearing loss that is severe or profound
-
Thyroid enlargement (hypothyroidism) that appears during childhood or early
adulthood
-
A positive perchlorate discharge (for thyroid
function).
Although these are the most common characteristics of hearing loss due
to mutations in SLC26A4, there can be variations, even within a family. SLC26A4 mutations
are usually thought to cause Pendred Syndrome, a genetic condition associated with
hearing loss and goiter (thyroid enlargement due to hypothroidism). However, mutations in the SLC26A4 gene can sometimes
cause hearing loss in people who do not have any thyroid problems. Also,
some persons with hearing loss do not have temporal bone abnormalities and some can have
mild or moderate hearing loss.
SLC26A4 Mutation Testing Procedures
A DNA sample is obtained and the SLC26A4 sequence is compared to that of
the regularly occurring sequence to look for changes. Some laboratories may
examine the entire coding sequence of the while other laboratories may only
search for the common mutations. There are 3 common mutations (L236P,
1001+1G>A, T416P) that cause over half of the cases of hearing loss associated
with this gene.
Interpretation of Results
There are three possible outcomes of an
SLC26A4 Mutation test:
1. No SLC26A4 mutations are detected. If no mutations are found, and the entire coding
sequence was analyzed, it is unlikely that the hearing loss is caused by
mutations in the SLC26A4 gene.
2. Two SLC26A4 mutations are detected. If two identical mutations or two different mutations are found, and these mutations have been previously found to cause
hearing loss, it can be assumed that the hearing loss is caused by these mutations in the SLC26A4 gene.
3. Only one SLC26A4 mutation is detected. If only one mutation is detected, interpretation can be difficult. It is possible that the test did not detect the
second mutation that the SLC26A4 mutation found may be unrelated to the hearing loss.
-
SLC26A4 (PDS) Gene Test
- Mitochondrial Gene Tests
-
COCH Gene Test
-
Cx30
Familial Propensities
for deafness
Children
If your son or daughter is deaf and the
reason has not been definitely found, his or her chance of having a deaf child
later on is fairly low (but it could still happen). Will additional children
have the same hearing impairment?
Occasionally, for example, in a family with some moderately deaf members there
can be one who is severely affected. Depending on personality, each child will
handle the deafness differently. One child (with hearing aids) can
find a moderate degree of deafness a minor problem and another child with an
almost identical audiogram (hearing test) may find it a much bigger problem.
Some books have given a figure of risk
about one-in-twenty, but it is not really known. However, if two people who are
known to have deafness marry, the chance that they will have deaf children is
significant (greater than 70%).
Siblings
Provided that it has been found that the
sibling has normal hearing, his/her chance of bearing a deaf child is a low
risk, although it is slightly higher than that of a person from a family with no
history of deafness.
In families with X-linked recessive
deafness, all the daughters of affected males will be carriers. There is a
one-in-four chance that male grandchildren will be deaf.
Thanks to Phil Wyatt at
www.hearingcentral.com for technical
consulting on this article