From
Epidemiology to Clinical Practice: The Connexin Connection
Aileen Kenneson, Coleen Boyle
Tables | Figures | References
Individuals who are deaf or hard-of-hearing account for a significant
portion of the population. Currently about one sixth of the U.S. population
(i.e. about 40 million individuals) have some degree of hearing loss,
a half of a million of which fall into the severe-to-profound range.(1)
Hearing loss may occur late in life, or may be present at birth, as
is the case for one to three in 1000 newborns.(2) Formerly,
these children were not diagnosed until they were two to three years
of age,(3) resulting in developmental delay, particularly
in the arena of language development.(4) However, recent
technological advances and increased public health attention have resulted
in the development of Early Hearing Detection and Intervention (EHDI)
programs in most of the United States. EHDI programs seek the early
identification of infants with hearing loss via universal newborn hearing
screening programs followed by linkage with appropriate intervention
options, of which there are many, resulting in the avoidance of developmental
delays.(4-6)
Genetic evaluations are often included as part of the medical care
of individuals with hearing loss. Based on family history and physical
examination, clinical geneticists categorize hearing loss into syndromic
and non-syndromic cases, a distinction that is useful both for appropriate
clinical care and estimation of recurrence rates.(7)
Recent advances in our understanding of single-gene causes of both syndromic
and non-syndromic hearing loss are likely to increase the role of specific
genetic tests in the evaluation of individuals with hearing loss.
As genetic research progresses and the demand for use of genetic testing
increases, genetic tests often move rapidly from research interest into
clinical use, sometimes before the clinical utility of the test is fully
defined.(8,9) This is the case for
GJB2, a gene recently implicated in up
to 50% of cases of non-academic hearing loss in some populations. Thus,
GJB2 testing may serve as a model by which
we can examine the translation of research advances into clinical and
public health use.
Background
Translation of sound waves into integrated neuronal signals in the brain
is an amazingly complex process, so it is not surprising that hundreds
of genes are involved in the development and operation of this machinery.(10)
Variation in any one of these genes can result in hearing loss. The
extent of locus heterogeneity of hearing loss is illustrated by the
more than 400 hereditary syndromes which claim hearing loss as a component,(11)
and which account for about 30% of cases of hearing loss.(12-14)
Heterogeneity is also observed in non-syndromic cases, which are typically
sensorineural in nature, and for which there is linkage evidence for
almost 70 loci, including autosomal recessive variants in 75-80% of
non-syndromic cases (designated with the prefix DFNB), autosomal dominant
variants in 20-25% (DFNA), and X-linked variants in 1-1.5% (DFN).(15)
The estimated numbers and types of loci for non-syndromic hearing loss
based on linkage analysis are: 30 autosomal recessive, 29 autosomal
dominant, 8 X-linked, and two mitochondrial.(16) The
Gap Junction Beta 2, GJB2,
gene was recently identified as the source of both the DFNB1 (autosomal
recessive) and the DFNA3 (autosomal dominant) loci.(17-20)
The GJB2 gene encodes for connexin 26,
a beta class gap junction protein expressed in the cochlea and in the
epidermis. Connexin 26 hexamers form channels between cells that, when
open, allow cell-to-cell diffusion of small molecules. This function
is necessary for the recycling of potassium in the cochlea that is critical
for sensorineural hearing function.(21) More than
90 variants of the GJB2 gene have been
reported, and many are rare; recessive alleles, dominant alleles, and
polymorphisms have all been described.(22)
Epidemiological Findings
Contribution of GJB2
Variants to Hearing Loss
A large number of studies related to the association between hearing
loss and GJB2 variants in a broad range
of populations have been published in the past few years. In general,
the conclusions are limited by factors such as small sample sizes, lack
of population-based ascertainment methods and lack of population descriptions.
For example, a common source of ascertainment is hearing loss clinics;
potential biases in this scenario include self-selection for clinic
attendance, and under-ascertainment of mild or unilateral hearing loss.
Ascertainment details are often not published, and reports often lack
population descriptions including age, sex, and race/ethnicity. Comparison
between studies is also limited by the differences in inclusion criteria,
which have included all familial cases, recessive cases, sporadic cases,
or all cases combined. However, despite the limitations, enough data
have been amassed that we can begin to develop a picture of the relationship
between GJB2 and hearing loss.
Given the extraordinary genetic heterogeneity of non-syndromic hearing
loss, it was believed that no single gene would play a significant role
in its etiology. So it was surprising to discover that sequence variations
at the GJB2 locus account for up to 50%
of cases of non-syndromic prelingual sensorineural hearing loss in some
populations. While more than 90 alleles have been described in the literature,
three account for the majority of GJB2-related
hearing loss in studied populations: 167ΔT, 35ΔG and 235ΔC,
the most common variant alleles in the Ashkenazi Jewish population(23,24),
populations of northern European descent(25-32), and
in the Korean(33) and Japanese(34-36)
populations, respectively.
Figure 24-1 summarizes data from several sources
and depicts the contribution of the GJB2
variants to hearing loss in several different populations around the
world. The available population-specific epidemiological data consistently
indicate population differences in two key measures that are important
to determine the clinical validity of genetic testing: (1) the percent
of cases of non-syndromic hearing loss that is associated with GJB2
variants, and (2) the population frequency of the different GJB2
alleles. For example, non-syndromic sensorineural hearing loss is associated
with GJB2 variants in almost 50% of cases
in Israel, but only 8% in Korea and 20% in Japan. Likewise, the 35ΔG
allele accounts for about 10-20% of cases of non-syndromic hearing loss
in persons of northern European descent, but about 30-40% of cases in
Mediterranean regions.
Table 24-1 presents the contribution of GJB2
variants to non-syndromic hearing loss in several populations. The table
presents both the percent of cases of hearing loss associated with GJB2
variants in general, as well as the percent of cases of hearing loss
that are associated with the most common allele in that population.
For example, in European and North American whites, 38% of individuals
with hearing loss carry one or more GJB2
variant allele, but 34% of individuals with hearing loss carry one or
more copies of 35ΔG. Thus, the 35ΔG allele accounts for the
majority of variant alleles in this population. In contrast, 50%
of Ashkenazi Jewish individuals with hearing loss carry a GJB2
variant allele, but only 31% carry at least one copy of the 167ΔT
variant. Thus, there is more allelic heterogeneity in the Ashkenazi
Jewish population than there is among European and North American Whites.
Table 24-1 also demonstrates that these alleles
are not uncommon in the general population. The 235ΔC allele is
carried by 1% of individuals in Korea and Japan, and the 35ΔG allele
is carried by 1 in 50 Whites. In the Ashkenazi Jewish population, the
167ΔT allele may be carried by up to 8% of the general population.
In general, there is a lack of phenotype data related to the contribution
of the less common GJB2 variants to hearing
loss. In addition, because of the small numbers of individuals with
mild, unilateral, and late-onset hearing loss included in studies, the
potential involvement of GJB2 variants
with the full spectrum of forms of hearing loss has not been fully assessed,
particularly in the case of the less common variants.
GJB2 Variants and Age of Onset
To fully assess the relationship between GJB2
variants and age of onset, genotype data is needed on individuals with
congenital (present at birth), non-congenital prelingual, postlingual,
and late-onset (after age 30) hearing loss. In the absence of newborn
hearing screening, hearing loss is usually not diagnosed until late
infancy or early childhood. Thus, in most published studies, it is not
possible to distinguish between congenital and non-congenital prelingual
hearing loss.
Only one published study has examined the contribution of GJB2
variants to congenital hearing loss. Allele-specific methods were used
to determine the prevalence of the 35ΔG and 167ΔT genotypes
in 42 infants identified with hearing loss through the Rhode Island
universal newborn hearing screen. The study identified three 35ΔG
homozygotes, two 35ΔG/167ΔT compound heterozygotes, and one
35ΔG carrier. The two compound heterozygotes were reported as having
Ashkenazi Jewish ancestry. The remaining newborns were of mixed European
background. Thus, the 35ΔG and 167ΔT genotypes in this newborn
population with hearing loss did not differ from other American populations
with hearing loss who were ascertained in childhood, and who were of
similar race/ethnicity (Table 24-1).(37)
More studies of this type, as well as studies including documented
non-congenital prelingual hearing loss, are needed to assess the relationship
between GJB2 variants and congenital hearing
loss. In this regard, it is important to note that there have been case
reports of newborns who passed the newborn hearing screen but were diagnosed
with GJB2-related hearing loss later in
infancy.(38,39) It is not clear
whether these cases represent false negative results of the newborn
hearing screening programs or are indicative of a non-congenital and/or
progressive nature of some GJB2-related
cases of hearing loss.
Only four studies have addressed the possibility of an association
between GJB2 variants and postlingual hearing
loss. Three of these studies did not detect any GJB2
variants among individuals with postlingual hearing loss, including
11 individuals in Israel (age of onset undefined)(24),
16 in France (onset before age 20)(26) and 39 in Japan
(onset between 3 and 30 years).(36) The fourth study,
taking place in Austria, found 4 carriers of GJB2
variants among 16 individuals with postlingual (undefined) hearing loss.(40)
The genotypes were L90P/I20T (onset in first decade), L90P/35ΔG
(onset in first decade), 35ΔG/+ (onset in first decade), and G160S/+
(onset in fourth decade). The L90P allele is of interest in this population
because it is seen in 2 of 16 postlingual cases, and 3 of 53 prelingual
cases of hearing loss. Thus, this allele may contribute to postlingual,
as well as prelingual, hearing loss. The failure to detect GJB2
variants in the other three postlingual studies may be due to a higher
prevalence of the L90P allele in the Austrian population, as this allele
was detected only rarely in individuals with hearing loss in France
(2 of 88)(26) and Italy (3 of 147)31,41, but not at
all in Israel (0 of 102)(23,24),
Japan (0 of 94)(34-36), Korea (0 of 147)(33),
Tunisia (0 of 70)(42) or the United Kingdom (0 of
210).(30)
Another allele, C202F, has also been implicated in postlingual hearing
loss, as it was observed to co-segregate with hearing loss (age of onset
between 10 and 20 years) over five generations in a French family.(43)
This allele was not detected in 95 French control individuals(43),
nor has it been reported in other studies that provided sequence data
on controls, including 100 Korean newborns(33), 209
Japanese individuals(34-36), and 119 additional French
individuals.(27)
No published studies have assessed the possible relationship between
GJB2 variants and late-onset (after age
30) hearing loss. Thus, additional population-based studies involving
individuals with congenital, non-congenital prelingual, postlingual,
and late-onset hearing loss will be needed to fully assess the relationship
between GJB2 variants and age of onset.
Factors Influencing Phenotypic Outcome
Many study groups have reported that the degree of hearing loss of individuals
with the same GJB2 genotype varies in severity,
even within sibships.(23,24,26,31) This
suggests that other factors, genetic and/or environmental, may be acting
to modify the phenotypic outcome of GJB2
variant alleles. Hearing loss is typically described as 50% genetic
and 50% environmental in nature, involving a wide range of both genetic
and environmental factors(12); any number of these
factors could potentially influence the phenotypic expression of GJB2
variant genotypes.
Influence of Environmental Factors
The possible contribution of environmental factors to GJB2-related
hearing loss has not been assessed. Most of the studies pertaining to
the contribution of GJB2 variants to hearing
loss excluded cases with known risk factors from the genetic analysis.
These factors include infections (e.g., meningitis, rubella), low birth
weight, ventilator use, ototoxic medications (e.g., aminoglycosides),
and hyperbilirubinemia. However, a case report of two individuals with
hearing loss originally attributed to rubella infection that were later
found to be homozygous for the 167ΔT variant 39 suggests that the
presence of known risk factors should not necessarily preclude genetic
analysis. Indeed, the proportion of GJB2
cases that have been attributed to other causes has not been elucidated,
and the possibility of gene-environment interactions has not been examined.
Studies pertaining to the relationship between GJB2
variants, environmental factors, and hearing loss may identify factors
that modify the GJB2 phenotype, and may
implicate GJB2 variants in the susceptibility
to known ototoxic factors. In addition to lending clues about the developmental
etiology of hearing function, studies of this nature are important for
accurate genetic counseling. For example, in the above case report,
the couple would have originally been counseled that the chance of having
a child with hearing loss was low due to the environmental nature of
their hearing loss. However in retrospect, it actually was 25% due to
the recessive nature of their alleles.
Contribution of GJB2 Variants to Syndromic Hearing
Loss
The currently published GJB2 studies have
generally excluded cases of syndromic hearing loss from analysis, thus
precluding the analysis of possible gene-gene interactions in the phenotypic
expression of these syndromes. One study in the United Kingdom included
DNA analysis of seven families with syndromic hearing loss. The DNA
analysis looked only for the 35ΔG allele, which was not detected
in any of these families.(44) The small number of
participants and the allele-specific DNA analysis limit any conclusions
about the role of GJB2 variants in syndromic
hearing loss.
Over 400 different recognizable syndromes have hearing loss as a component,
varying in degree of loss, age of onset, and penetrance.(11)
The aforementioned variation in degree of hearing loss in siblings with
identical GJB2 genotypes indicates the
importance of genetic and/or environmental backgrounds in the expression
of GJB2-related hearing loss. Hence, it
is also possible that variants in genes such as GJB2
influence the penetrance and expressivity of hearing loss associated
with syndromes. This possibility remains to be explored.
Laboratory Detection Techniques
The known genetic variants in the GJB2
gene are amenable to detection by standard molecular genetic laboratory
techniques. The majority of GJB2 variants
fall in the 680-basepair coding region in exon 2, and the rest fall
in the 3’ untranslated region in exon 1. Detection methods include
allele-specific PCR-based methods, scanning technologies such as SSCP,
and sequencing. As some common alleles account for the majority of variants
in some populations, allele-specific methods are often used, either
alone or in conjunction with sequencing methods. A recent survey of
laboratory practices pertaining to clinical use of GJB2
testing indicated that U.S. laboratories vary in their chosen methodology.
Most of the laboratories used sequencing, either alone or as a follow-up
to allele-specific methods. Of the laboratories that employed sequencing,
most analysed exon 2 only, while a few sequenced both exons 1 and 2.(45)
Most of the published studies that have utilized sequencing methods
have included analysis of exon 2 only. Therefore, information is lacking
to accurately determine the relative clinical validity and utility of
these two methods.
Potential Contribution Of Genetic Information To Improved
Health Outcomes
The American College of Medical Genetics
recommends the provision of genetic services to individuals with hearing
loss “to establish the etiology whenever possible”(46),
and GJB2 testing may be one potential option
in this process. Several potential clinical uses of GJB2
testing in children with hearing loss have been proposed, including
(1) ruling-out risk of syndromic complications, (2) predicting moderate-to-profound
hearing loss requiring aggressive language intervention, (3) indicating
potential candidacy for cochlear implants use, and (4) allowing genetic
counseling regarding recurrence rates.(37,47,48)
However, there is little evidence in support of some of these proposed
uses, and there are many factors to be weighed in the decision to include
GJB2 testing.
Much of the information regarding a child’s phenotype can be
obtained through physical examination by audiologists, otolaryngologists
and clinical geneticists, so a child’s course of intervention
may or may not be significantly altered by the knowledge of GJB2
genotype. It has been argued a GJB2 diagnosis
may reduce the burden of additional tests that are traditionally used
to rule-out syndromic complications (e.g., ophthalmologic, cardiac,
vestibular evaluations).(48) This may be particularly
relevant in the case of infants with hearing loss, as the medical tests
used to distinguish syndromic and non-syndromic cases may not have as
much predictive power during infancy as they do later in childhood.
However, the potential role of GJB2 variants
in the penetrance and expressivity of hearing loss in syndromes has
not been assessed, so while the presence of GJB2
variants in a newborn with hearing loss will most likely be associated
with non-academic hearing loss, more data need to be collected to determine
the sensitivity and specificity of this use of GJB2
testing. Likewise, the use of GJB2 testing
in the prediction of the success of various intervention options has
not been assessed.
Determination of a genetic etiology also allows for the provision of
recurrence information for the family. However, organizations of professional
geneticists, including the American Society of Human Genetics and the
American College of Medical Genetics, generally discourage the
genetic testing of minors in the absence of direct intervention benefits
for the child.(49) Given the Deaf community’s
concerns about genetic testing(50), this point is
particularly germane in regards to hearing loss because a child may
prefer not to know this information as an adult.
Another factor to be considered in the decision to use GJB2
testing is the lack of epidemiological data pertaining to the less common
variants. This paucity of information must be considered when counseling
families about GJB2 test options and results.
Consider, for example, the M34T allele. In 1997, the M34T variant was
found to co-segregate with 3 generations of hearing loss in one family
in an apparently dominant fashion.(20) This was the
first evidence implicating GJB2 in non-syndromic
hearing loss. But several years later, a second variant was characterized
in this family, found in trans with the
M34T allele in the individuals with hearing loss.(51)
This suggests that the M34T allele is recessive in nature. Since then,
several groups have documented the failure of M34T to co-segregate with
hearing loss in several families, raising the possibility that M34T
may be a benign polymorphism.(52-55) More recent evidence
that supports the recessive allele model includes the observation of
M34T compound heterozygotes and homozygotes among individuals with hearing
loss but not among control populations.(51-60) This
example cautions researchers and clinicians to interpret the role of
less common, and hence less-well-characterized, variants with care,
particularly in regards to family genetic counseling issues.
These issues will continue to affect an increasing number of families
as an increasing number of states are screening newborns for audiologic
function so that infants with hearing loss are identified and referred
for intervention services very early in life. The role that GJB2
testing will play in conjunction with EHDI programs is still in the
process of being defined.
Conclusions
Several areas of current research are aimed at the definition of the
clinical utility of GJB2 genetic testing.
One such area of research focuses on the potential role of GJB2
genotyping in the prediction of success of various intervention options,
such as cochlear implants. A second area of research involves the contribution
of GJB2 variants to hearing loss in diverse
populations. Given the inter-population variability of the prevalence
of GJB2 variants and their apparent contribution
to hearing loss, it is would be helpful to define these measures in
all potential target populations. In the United States, for example,
there is a lack of data pertaining to non-White American populations.
Epidemiological data specific to these populations are necessary to
provide population-specific determinations of clinical validity and
utility.
While GJB2 variants have been shown to
be associated with a large fraction of cases of non-syndromic moderate-to-profound
prelingual hearing loss, the potential contribution of GJB2
variants to mild, unilateral, late-onset, syndromic, or environmentally-acquired
cases of hearing loss has not yet been determined. Research into potential
associations such as these may help to unravel the interactions between
genetic and environmental influences in the phenotypic expression of
hearing function and hearing loss.
The emergence of EHDI programs presents an excellent opportunity for
population-based ascertainment of cases of congenital hearing loss.
Similar population-based strategies are needed for complete ascertainment
of cases of hearing loss arising sometime after the newborn period.
Inclusion of all cases of hearing loss, regardless of etiology (syndromic
versus non-syndromic, other known genetic factors), presence of known
risk factors, degree of hearing loss, and age at onset are required
to fully assess the contribution of the GJB2
gene to the spectrum of hearing loss phenotypes. In addition, as greater
than 5% of the general population have a hearing loss of some kind(61),
the ascertainment of control populations should also be carefully considered
in this type of analysis, and should include individuals known not to
have a hearing loss. Confounding variables including age, sex, race/ethnicity,
and presence of known risk factors are important considerations in case-control
analyses of GJB2 variants and hearing loss.
A final note about the process of defining the potential role of genetic
testing in medical practice relates to the consideration of the viewpoints
of all stakeholders. The case of genetic testing pertaining to hearing
loss has raised some important issues in this regard. The goal of the
medical community to eliminate disease and disability is at odds with
the viewpoint of the Deaf community that hearing loss is not a disability.
This viewpoint challenges society to reconsider the definitions of disease
and disability. The Deaf community has also expressed concerns that
genetic testing will do more harm than good and will devalue individuals
with hearing loss.(50) The issues raised by the Deaf
community provide a unique opportunity by challenging scientists and
society to find culturally-sensitive methods for genetic research and
testing that are acceptable to all cultural groups.
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