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Connexin 26 Gene Mutations in Congenitally Deaf Children
Pitfalls for Genetic Counseling
Sandrine Marlin, MD, PhD;
Éréa-Noël Garabédian, MD;
Gilles Roger, MD;
Lucien Moatti, MD;
Nicole Matha, MD;
Patricia Lewin, MD;
Christine Petit, MD, PhD;
Françoise Denoyelle, MD, PhD
Arch Otolaryngol Head Neck Surg. 2001;127:927-933.
ABSTRACT
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Objective To evaluate difficulties encountered in genetic counseling in deaf children
carrying connexin 26 gene (CX26 or GJB2) mutations.
Design Prospective study.
Setting Outpatients, tertiary referral center.
Patients Ninety-six unrelated deaf children in whom CX26 mutations
had been detected consecutively. Children were recruited to a center for genetic
counseling for deaf children, and all had congenital deafness, sporadic or
familial.
Results In 63 children, deafness was clearly a DFNB1 form with autosomal recessive
inheritance: 47 of the 63 were homozygous for the most frequent mutation,
the deletion of G at position 35 (35delG); 16 of 63 carried on
both alleles of CX26 frameshift or stop mutations, or missense
mutations affecting a critical region of the gene. In 33 of 96 children, genetic
counseling was difficult: 21 of 33 had a single mutation detected, 11 of 33
had new missense mutations or mutations whose pathogenicity remains debated
in the literature, and 1 of 33 had a genotype with both a recessive mutation
(35delG) and a mutation acting as a dominant mutation.
Conclusions Interpretation of results for the molecular diagnosis of mutations in
the connexin 26 gene is difficult in almost one third of cases. Close collaboration
between geneticists familiar with deafness and otolaryngologists is essential
to provide a high standard of genetic advice.
INTRODUCTION
SENSORINEURAL DEAFNESS present at birth affects 1 child in 1000 in developed
countries.1 Until a few years ago, genetic
forms were thought to account for 30% to 45% of cases of congenital deafness,
about two thirds of these cases being isolated, ie, nonsyndromic, genetic
forms.2-4 The remaining
cases were attributed to environmental causes (27%-35%) or considered sporadic
cases of deafness for which no cause had been identified (25%-35%).2-4
In 1997, an unexpected discovery concerning nonsyndromic forms modified
the knowledge of the causes of congenital deafness and provided a new tool
for investigating these causes. The nonsyndromic genetic cases are mainly
autosomal recessive forms (DFNB forms). Twenty-eight DFNB genes (called DFNB1 to DFNB29) have so far been mapped to the human chromosomes; 7 of them
are identified,5 one of which is the connexin
26 gene (CX26 or GJB2) underlying
the DFNB1 form.6 We
and others showed in 1997 that this gene, CX26, was
responsible for half of the DFNB forms in a multicentric analysis performed
on families from France, the United Kingdom, and New Zealand, and in a study
of families from Spain and Italy.7-9
One specific mutation, 30delG, actually referred
to as 35delG (the deletion of G at position 35),
creating a frameshift at the beginning of the protein, was found to account
for about 70% of all CX26 mutations.7
Studies of the prevalence of 35delG in Mediterranean
countries and the United States showed that this mutation has a high prevalence
in the control population (normal-hearing heterozygous carriers, 2%-4%), similar
to that of the most frequent disease mutation reported to date, the  F508 mutation of the cystic fibrosis transmembrane conductance
regulator gene responsible for cystic fibrosis.9-12
Two other CX26 mutations are highly prevalent in
other populations: the deletion of T at position 167 (167delT) in Ashkenazi Jews (4%) and the deletion of C at position 235 (235delC) in Japan (1%-2%).13-15
In a prospective analysis performed on families from France, we observed
that 51% of the families with prelingual DFNB forms of deafness were DFNB1
forms caused by biallelic CX26 mutations.16 Moreover, we showed that DFNB1 forms accounted for
31% of the sporadic cases of congenital deafness classified as being of unknown
origin. We can estimate that the majority of congenital cases of deafness
are genetic autosomal recessive forms. These data demonstrate the value of
looking for CX26 mutations in sporadic cases to document
the genetic nature of the disorder and thereby inform the families of the
risk of other affected children.
New epidemiologic studies of factors causing congenital deafness will
have to consider this high proportion of DFNB1 forms among sporadic cases
and to include, in the etiologic evaluation, the search for CX26 mutations.
Molecular diagnosis of CX26 mutations is now
available in the majority of developed countries, and this new ability to
investigate the etiology of congenital deafness has profoundly modified daily
medical practice. This test forms part of the investigations of the etiology
of congenital deafness, as long as the families agree to it. After clinical
examination and laboratory tests to identify an extrinsic cause or a syndrome
associated with the deafness (see the "Patients and Methods" section), the
molecular diagnosis of CX26 mutations can be proposed
if the phenotype of the deafness is compatible with DFNB1 forms: nonsyndromic
congenital deafness with no associated radiologic anomaly of the inner ear
and no vestibular symptoms (walking before 18 months, no episode of vertigo,
and, if available, normal results of vestibular caloric tests).16
However, detection of CX26 mutations does not
always indicate the involvement of the gene in the cause of the deafness:
some deaf patients only have a mutation on one allele, while others have mutations
that are not known to be definitely pathologic. Clinicians treating deaf children
must be aware of these diagnostic pitfalls and be very careful in the information
they provide to the families. We detail in this prospective study the various
mutations found in 96 unrelated families. The interpretation of the results
are discussed to help genetic counseling in deaf individuals carrying CX26 mutations.
PATIENTS AND METHODS
PATIENTS
We recruited patients from genetic counseling consultation for deaf
people at the Pasteur Hospital and at the Armand-Trousseau Children's Hospital,
Paris, France, from September 1, 1997, through December 31, 1999. The CX26 mutations were identified in 96 unrelated families
(126 deaf subjects tested for CX26 mutations) affected
by a nonsyndromic mild to profound prelingual deafness (ie, with a supposed
onset before 2 years of age). Forty-six families had a single deaf child (sporadic
case of deafness). Affected members had mild deafness in 4 families, moderate
in 8, severe in 13, and profound in 55, and 16 families had members with different
degrees of deafness. In 50 families, 2 or more individuals were affected:
47 (74 deaf individuals) had an autosomal recessive, 1 an autosomal dominant
(2 deaf individuals), and 2 an uncertain mode of inheritance (4 deaf individuals).
METHODS
The protocol of this prospective study was accepted by the Consultative
Committee for People Protection in Biomedical Research according to the French
legislation, and informed consent was obtained from all subjects and from
parents of underaged patients.
In each patient, a complete medical history was obtained to determine
the age at onset of deafness and to exclude the possibility of environmental
causes, such as maternofetal infection, perinatal complications, meningitis,
mumps, prenatal or postnatal drug ototoxic effects, and acoustic trauma. The
deaf subjects underwent an otoscopic and a general examination with a systematic
search for signs suggestive of a syndromic form of deafness (especially dysmorphism,
integumentary disorders, and branchial, cardiac, and thyroid anomalies). They
also underwent an ophthalmologic evaluation (including funduscopy) and a search
for hematuria and proteinuria.
Deaf children and their parents underwent pure-tone audiometry with
a diagnostic audiometer in a soundproof room, with recording of pure-tone
air- and bone-conduction thresholds. Air-conduction pure-tone average (ACPTA)
threshold in the conversational frequencies (0.5, 1, and 2 kHz) was calculated
for each deaf ear and was used to define the severity of deafness: mild (20
dB<ACPTA 39 dB), moderate (40 dB<ACPTA69 dB), severe (70 dB<ACPTA89
dB), or profound (ACPTA  90 dB). The severity of deafness in each child
was defined by the degree of hearing loss for the best ear.
Blood samples were obtained from deaf children and their parents, and
the DNA was extracted. The entire coding phase of CX26
(exon 2) and flanking acceptor splicing site were amplified by polymerase
chain reaction, with the use of primers GAP1F (5'-CCTATGACAAACTAAGTTGGTTC-3')
and P50, antisense (5'-GACAGCTGAGCACGGGTTGCCTC-3'). The CX26 exon 1 and flanking donor splicing site were amplified
with primers PP18 (5'-TCCGTAACTTTCCCAGTCTCCGAGGGAAGAGG-3') and
PP21, antisense (5'-CCCAAGGACGTGTGTTGGTCCAGCCCC-3'). The polymerase
chain reaction products were sequenced. Experimental conditions for polymerase
chain reaction and sequencing were as previously described.7
After January 31, 1999, the molecular diagnosis of CX26 mutations was performed by the Laboratory Pasteur-Cerba, Cergy-Pontoise,
France, by the same methods.
A set of control DNA samples from 116 unrelated individuals living in
France (232 chromosomes) was screened for mutations in the coding part of CX26.
RESULTS
RESULTS IN DEAF INDIVIDUALS FROM THE 96 AFFECTED FAMILIES
Considering 1 deaf individual in each family and allowing 1 independent
allele in the 2 consanguineous families, we found 169 of 190 mutated alleles,
and the 35delG mutation accounted for 75.1% (127/169)
of the mutated alleles.
Deafness was clearly of a DFNB1 form in 63 (65.6%) of the 96 families.
In 47 of these 63 families, deaf individuals were homozygous for the 35delG mutation. The homozygous genotype 35delG was detected in 27 (58.7%) of the 46 families with autosomal
recessive mode of inheritance, 18 (38.3%) of the 47 families with a sporadic
case of deafness, and 2 of 2 families with uncertain mode of inheritance.
In 16 of 63 families, deaf individuals carried, on both alleles, mutations
considered to be pathologic because they either produced a premature stop
codon or affected the splicing site or initiator codon (Table 1).
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Table 1. Biallelic Mutations in 63 of 96 Families Indicating DFNB1-Type
Deafness*
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In the remaining families (33/96), genetic counseling was difficult:
deaf individuals had either mutations on a single allele (21 families) or
biallelic mutations of which one or both were missense mutations of uncertain
pathogenicity (12 families) (Table 2).
One of these 12 families had a dominant mode of inheritance: the profoundly
deaf child was compound heterozygous 35delG/P175T,
and the heterozygous P175T (C to T at nucleotide 523) mutation was associated
with deafness in the father and grandmother (Figure 1).
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Table 2. Mutations Detected on a Single Allele and Missense Mutations
on One or Both Alleles in 33 of 96 Families*
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Figure 1. Pedigree of the family with a
dominant mode of inheritance and audiometric curves correlated to the genotype.
Solid symbols represent congenitally deaf individuals; open symbols, unaffected
individuals; and plus signs, the wild-type allele. In audiometric curves,
the dashed line represents the right-ear air conduction threshold and the
solid line, the left-ear air conduction thresholds.
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RESULTS IN PARENTS OF DEAF INDIVIDUALS
In each case, the mutations found in deaf individuals were also present
in the parents who were heterozygous carriers. However, 5 normal-hearing parents
of children homozygous for 35delG had mutations on
both alleles of the connexin 26 gene: 35delG/V153I
(2 cases), 35delG/M34T (2 cases), and 35delG/R127H (1 case), suggesting that a polymorphism is associated
with the 35delG mutation. The normal-hearing father
with the 35delG/R127H genotype had a congenitally
deaf mother carrying 35delG/V37I mutations. The pedigree
and audiometric data in this family and in the other family with an uncertain
mode of inheritance are detailed in Figure
2.
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Figure 2. Pedigrees and genotypes of the
2 families with uncertain mode of inheritance. Solid symbols represent congenitally
deaf individuals; open symbols, unaffected individuals; and plus signs, the
wild-type allele. In audiometric curves, the dashed line represents the right-ear
air conduction threshold and the solid line, the left-ear air conduction thresholds.
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ANALYSIS OF CONTROL INDIVIDUALS
Of 116 control subjects, 2 were heterozygous carriers of V27I (G to A at position 79) (carrier frequency, 1.72%), 1 of V37I (G to A at position 109) (0.86%), and 1 of M34T (T to C at position 101) (0.86%). The 35delG mutation was not detected in this sample.
COMMENT
The data presented herein point out the difficulties encountered in
interpreting the result of molecular diagnosis in about one third of the families
carrying CX26 mutations. Deaf individuals in these
families carry either mutations whose pathogenicity is uncertain on one or
both alleles of CX26, or a single mutated CX26 allele.
The 35delG mutation is detected in about three
fourths of the mutated alleles, which is similar to the proportion reported
in other studies in white populations. Because of the high prevalence of 35delG heterozygous carriers in the general population,
pedigrees with false dominance (Figure 1)
should suggest a DFNB1 form of deafness.
To date, descriptions of 49 CX26 mutations
found in deaf individuals have been published in the literature, including
the 3 new missense mutations (R32H [G to A at position
95], R32C [C to T at position 94], and N206S [A to G at position 617]) detected in this study in association
with the 35delG mutation.7-11,13-24
The pathogenicity of the stop or frameshift mutations (including the mutations
reported in Table 1), usually
leading to a protein truncated before the third transmembrane domain, is highly
probable.
The pathogenicity of missense mutations is more difficult to determine.
Segregation analysis with the polymorphic markers of DFNB1 has not been performed
systematically in the families carrying this type of mutation.7-11,13-24
These mutations are usually presumed to be pathologic when they affect amino
acids conserved among connexins and when they are not detected in the general
population. Three CX26 missense mutations (M34T, W44C [G to C at position
132], and W77R [T to C at position 229]) have been
tested in in vitro expression systems (Xenopus oocytes
or noncommunicating HeLa cell models), showing impaired intercellular coupling
and abnormalities of trafficking and targeting of the connexin 26.25-26 However, the problems encountered
in the interpretation of the M34T mutation (see below)
point out the difficulty in extrapolating in vitro functional results to the
consequences of the mutation in vivo.
The results of this study allow better interpretation of the significance
of certain missense mutations. The mutations R127H
(a C-to-T transition at position 523 that creates a proline-to-threonine substitution
at codon 175), V153I (G to A at position 457), and M34T were detected in association with the 35delG mutation on the other allele in normal-hearing parents, and
one can regard these changes as polymorphisms. As found in 2 families in this
study (Table 1), R127H has been previously described in deaf patients as the sole mutation
found in CX26, and this change affects a residue
that is not highly conserved among ß-connexins.9, 23
This is in keeping with the nonpathogenic nature of this mutation.
The V153I mutation was not detected in our
study in the control population but was associated with a 35delG mutation in one deaf child with a sporadic case of deafness.
We decided that this change was not a causative factor in the deafness.
The effect of the M34T mutation continues to
be debated. It was first described as a dominant mutation,6
and functional studies in in vitro expression systems support the hypothesis
of dominant negative effect.25-26
However, several authors described normal hearing in M34T heterozygous carriers, and M34T presented
as a recessive mutation in one family.17, 20
The current evidence is in favor of M34T being a
polymorphism. Heterozygous carriers are found in the control population, with
a carrier frequency of 1% to 2.9% (0.86% in this study).17, 20, 27
Despite this high prevalence in the general population, deaf subjects homozygous
for M34T have not been described in the series published
to date, except the case reported herein (one deaf individual with a sporadic
deafness). Moreover, we report herein for the first time, to our knowledge,
that 2 subjects (parents of deaf children) who were compound heterozygotes
(M34T/35delG) had normal hearing.
Another pitfall in genetic counseling is highlighted by the pedigree
shown in Figure 1. The P175T mutation acts here as a dominant mutation. Involvement of this
mutation in deafness is probable: first, P175T has
never been described in control populations, and second, the proline at codon
175 is highly conserved among human, rat, and Xenopus
connexins and is located in the second extracellular loop, which is the major
determinant for compatibility between connexins.28
However, in the family described herein, we cannot exclude the possibility
that P175T is a recessive mutation and that the father's
and grandmother's deafness are due to another cause. We consider that there
is no indication to search for CX26 mutations in
families affected by autosomal dominant deafness when the affected members
have a similar deafness phenotype. However, we sometimes encounter pedigrees,
as shown in Figure 1, in which 2
or more very different deafness phenotypes coexist: we can suspect different
causes of deafness in the same family and consider that deafness can be a
DFNB1 form in congenitally affected members. The search for CX26 mutations is warranted in those cases.
The role of the V37I mutation is also contentious.
This mutation, described as a polymorphism, has a high prevalence in the general
population in Japan (1%-3% of the control alleles) and has a similar frequency
in alleles of congenitally deaf individuals (1/70 [1.4%]).14-15
In our series, V37I was homozygous in 2 sporadic
cases, one of which was associated with parental consanguinity and the other
associated with 35delG. Rabionet et al23
described another homozygous V37I sporadic case of
deafness, and V37I was not detected in the control
subjects from Italy and Spain. The V37I mutation
has been identified here in 6 (3.6%) of 169 mutated alleles from deaf subjects
(taking into account a single mutated allele in a case of consanguinity) and
1 (0.4%) of 232 alleles in our control population. Screening of very large
samples of control population is needed to determine the frequency of V37I heterozygous carriers in the general white population
and to determine the status of this mutation.
In the group of mutations associated with 35delG
in deaf children, we identified, in addition to the V37I and P175T mutations, a previously described
mutation, L90P (T to C at position 269),16 which has also been reported in Spain and Italy in
0.7% of the CX26 alleles from deaf individuals23 and never in control populations. In this group we
also detected 3 novel changes, and their involvement in disease can be assumed: R32C, R32H, and S139N (G to A at position 416) affect amino acids that are highly conserved
among connexins and located in the first (R at position 32) and third (S at
position 139) transmembrane domains. These mutations have never been detected
in control populations in the literature or in the present study.
Finally, in the group of 21 families in which deaf individuals had a
single CX26 mutation, we detected, in addition to
the 35delG mutation (11 families) and the 3 mutations M34T, V37I, and R127H (7 families) whose importance was discussed already, the V27I and E114G (A to G at position
341) polymorphisms highly prevalent in Japan (detected in 36%-39% and 24%-28%
of the Japanese control alleles14-15)
and 2 new mutations, N206S and M163V (A to G at position 487). The N206S
mutation affects an asparagine conserved among connexins and located in the
fourth transmembrane domain, and M163V, a methionine
of the second extracellular loop, conserved among ß-connexins. Their
pathogenicity is yet to be established given the absence of any identified
mutation on the other CX26 allele and of families
in whom the segregation of the mutation and the deafness can be studied.
Among the families with only one detected mutation, the majority (14/21)
were cases of sporadic deafness. Moreover, 7 of 21 families had an autosomal
recessive deafness, but in 3 of these 7 families, only 1 of the 2 deaf children
had the mutation (two 35delG heterozygotes and 1 R127H heterozygote). If one compares the group of 21 families
with only 1 detected mutation with the group of 47 families homozygous for 35delG, the proportion of sporadic deafness or familial
discordance was significantly different (17/21 [81%] vs 18/47 [38%]; P = .01). The involvement of the CX26 gene is not likely in the majority of these families.
The molecular diagnosis of CX26 has substantially
improved genetic counseling for hearing impairment, because it allows the
identification of a genetic cause to be established in many sporadic cases
for which an etiologic diagnosis had been impossible before.
The discovery in a deaf patient of a biallelic stop or frameshift mutation
allows the clinical geneticist to assert the genetic nature of the hearing
loss, to establish recurrence risks, to reassure the patient that the defect
is isolated, and to detect possible heterozygous relatives. The identification
of the role of CX26 in the etiology allows the clinician
to predict a low risk of progression of the hearing defect.16
However, at this time, this molecular diagnosis cannot guide the approach
to treatment and rehabilitation. In the future, it will be imperative to compare
the results of different treatments with the genotype.
On the contrary, the identification of biallelic mutations considered
to be polymorphisms allows one to rule out a role for CX26 in the cause of the audiologic defect and to search for another cause.
Genetic counseling becomes much more difficult when the molecular diagnosis
shows only a monoallelic mutation or biallelic mutations for which the pathogenicity
has not been proved in the absence of familial segregation analysis. If biallelic
missense mutations are found in a deaf individual, the clinical geneticist
could be helped by looking at CX26 mutations in both
parents to determine if these mutations were inherited from 2 different chromosomes.
The pathogenicity of a mutation could be established by the CX26 genotyping of hearing or deaf relatives of the proband. In these
cases, the definition of the phenotype becomes very important. To prevent
situations where interpretation is difficult, a molecular diagnosis should
be proposed only after checking that the phenotype is compatible with a role
for CX26. However, if the phenotype is compatible
and if the pathogenicity of the mutations could not be determined, the clinician
has to be very careful with respect to the cause of the hearing impairment,
and other genetic tests should be performed when possible.
With the advent of the molecular diagnosis of CX26 mutations, new mutations are being described every month, and the
status of many of the previously reported missense mutations remains uncertain.
Clinical geneticists, otolaryngologists, and audiologists are all likely to
be confronted with results, the interpretation of which will be difficult.
The various medical specialists who treat deaf children must be aware of these
difficulties and be very careful about what information they provide the families.
AUTHOR INFORMATION
Accepted for publication February 6, 2001.
Presented at the 15th annual meeting of the American Society of Pediatric
Otolaryngology, Orlando, Fla, May 17, 2000.
Corresponding author and reprints: Françoise Denoyelle, MD,
PhD, Service d'ORL Pédiatrique et de Chirurgie Cervicofaciale, Hôpital
d'Enfants Armand-Trousseau, AP-HP, 26 avenue du Dr Arnold Netter, 75571 Paris
CEDEX 12, and Université Paris VI, 4 Place Jussieu, 75252 Paris CEDEX
05, France (e-mail: f.denoyelle{at}trs.ap-hop-paris.fr).
From the Service d'ORL Pédiatrique et de Chirurgie Cervicofaciale,
Hôpital d'Enfants Armand-Trousseau, and Université Paris VI,
Paris, France (Drs Marlin, Garabédian, Roger, Moatti, Matha, and Denoyelle);
Laboratoire Pasteur-Cerba, Cergy-Pontoise, France (Dr Lewin); and Unité
de Génétique des Déficits Sensoriels, Institut Pasteur,
Paris (Dr Petit).
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