Download DEAFNESS and GENETIC COUNSELLING

DEAFNESS
and
GENETIC
COUNSELLING
Kim Frumar
Genetic Counsellor
BACKGROUND
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Hearing loss is the most common birth defect and the
most prevalent sensorineural disorder in developed
countries
1 in 500 newborns have bilateral permanent
sensorineural hearing loss and by adolescence it
increases to 3.5 per 1000
More than 50% pre-lingual deafness is genetic
Hearing loss increases with age- impact of both
genetics and environment and interactions between
environment and genetic predisposition
Causes of pre-lingual deafness
Single gene disorders
SYNDROMIC
 Associated with
malformations
external ear or other
organs
 Medical probs
involving other
organ systems
NON-SYNDROMIC
 No visible
abnormalities
external ear
 May have
abnormalities middle
and/or inner ear
 No associated
medical probs.
Syndromic hearing loss
Accounts for up to 30% of prelingual
deafness
 or deafness can occur later
 Abnormalities in other organ systems:

• can be obvious or subtle
• may be congenital
• may develop later
Syndromic
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Over 400 syndromic causes of hearing
loss
Autosomal dominant
Autosomal recessive
X-linked
Mitochondrial
Autosomal dominant
inheritance
only one copy of
altered gene needed
to be deaf
 passed down
through generations
 can occur as a
spontaneous
mutation in an
offspring of
unaffected parents

Autosomal dominant pedigree
I
Deaf
Dd
dd
II
Dd
Dd
Dd
Dd
III
ãMCRI Education Unit and Gene CRC
Autosomal recessive
inheritance
Need 2 faulty genes to
be deaf (one from each
parent)
 Deaf offspring can arise
from hearing parents
 2x AR Deaf parents
have 100% chance of
Deaf child
Autosomal recessive pedigree

I
Dd
Dd
1
2
Deaf
II
1
2
3
Dd
dd
DD
ãMCRI Education Unit and Gene CRC
X-Linked Inheritance
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Gene fault on X
chromosome
condition occurs more
frequently in males than
females
• males only have one
X- chromosome- no
backup copy
• females have two
X- chromosomessome backup
X-Linked Recessive Pedigree
X-linked
Deafness
XY
XX
XY
X cY
XY
X cX
X cX
X cX
X cY
XY
X cY
Mitochondrial inheritance
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Mitochondria• small structures within cells
• provide energy for the cell
• own set of 37 genes separate from 3040,000 genes in nucleus of the cell
• only the egg (not the sperm) contributes
mitochondria to the developing embryo
• Only females will pass mitochondrial traits
to their children
cytoplasm
mitochondrion
ribosomes
nucleus
chromosome
Autosomal dominant syndromes
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Waardenburg syndrome:
• most common AD syndromic hearing loss
• variable degrees of sensorineural hearing loss
• pigmentary abnorms. of skin, hair (white forelock)
and eyes (since people dye their hair, need to ask
about white forelock specifically).
• 4 types- WSI, WS II, WS III, WS IV
• several mutations identified and some molecular
genetic testing available
Autosomal dominant pedigree
I
Deaf
Dd
dd
II
Dd
Dd
Dd
Dd
III
ãMCRI Education Unit and Gene CRC
Autosomal dominant syndromes
Autosomal dominant pedigree
I
Deaf
Dd
dd
II

Branchio-oto-renal syndrome:
Dd
Dd
Dd
Dd
III
ãMCRI Education Unit and Gene CRC
• second most common type of AD syndromic
hearing loss
• Conductive, sensorineural & mixed hearing loss
• branchial cleft cysts or fistulae
• malformations external ear inc. preauricular pits
• renal anomalies
• 40% have mutations in EYA1 gene (chromosome
8q13)
• Molecular testing available
Autosomal dominant syndromes
Autosomal dominant pedigree
I
Deaf
Dd
dd
II
Dd
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Neurofibromatosis type 2 (NF2):
Dd
Dd
Dd
III
ãMCRI Education Unit and Gene CRC
• associated with a rare potentially treatable type of
deafness
• hearing loss secondary to bilateral vestibular
schwannomas
• hearing loss not usually until 3rd decade
• Molecular genetic testing available for presymptomatic at-risk family members to facilitate
early diagnosis and treatment
Autosomal dominant syndromes
Autosomal dominant pedigree
I
Deaf
Dd
dd
II
Dd
Dd
Dd
Dd
III
ãMCRI Education Unit and Gene CRC
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Stickler syndrome:
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progressive sensorineural hearing loss
cleft palate
spondylo-epiphyseal dysplasia and osteoarthritis
3 types recognized- 2 types include severe
myopia and predisposition to retinal detachment.
• molecular genetic testing available
Autosomal recessive syndromes
Autosomal recessive pedigree
I
Dd
Dd
1
2
Deaf
II
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Usher syndrome:
•
•
•
•
•
•
1
2
3
Dd
dd
DD
ãMCRI Education Unit and Gene CRC
most common type of AR syndromic deafness
dual sensory losses
congenital sensorineural hearing loss
later development of retinitis pigmentosa
affects over 50% of people who are deaf-blind
3 types- molecular testing only available for some
types
Autosomal recessive syndromes
Autosomal recessive pedigree
I
Dd
Dd
1
2
Deaf
II
1
2
3
Dd
dd
DD
ãMCRI Education Unit and Gene CRC
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Pendred syndrome:
• second most common type AR hearing loss
• congenital severe to profound sensorineural
hearing loss
• abnormality of bony labyrinth
• euthyroid goitre develops in early puberty
• Molecular genetic testing available
Autosomal recessive syndromes
Autosomal recessive pedigree
I
Dd
Dd
1
2
Deaf
II
1
2
3
Dd
dd
DD
ãMCRI Education Unit and Gene CRC
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Jervell-and Lange-Nielson syndrome:
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third most common type AR hearing loss
Congenital deafness
ECG abnorms- Prolonged QT interval
Syncopal episodes and may have sudden death
High risk children-those with F/H of sudden death,
SIDS, syncope, long QT syndrome- should have
thorough cardiac evaluation
• Genetic testing available for high risk individuals
Autosomal recessive syndromes
Autosomal recessive pedigree
I
Dd
Dd
1
2
Deaf
II
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Biotinidase deficiency:
1
2
3
Dd
dd
DD
ãMCRI Education Unit and Gene CRC
• caused by deficiency in biotin , a water-soluble Bcomplex vitamin essential for gluconeogenesis,
fatty acid synthesis and breakdown of some
amino-acids
• Mammals cannot synthesise biotin so rely on diet
and endogenous turnover of free biotin
• Deficiency leads to neurological problems, visual
problems and sensorineural hearing loss
• Diet and treatment should be initiated as soon as
possible
X-linked Syndromes
X-Linked Recessive Pedigree
X-linked
Deafness
XY
XX
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Alport syndrome:
XY
X cY
XY
X cX
X cX
X cX
X cY
XY
X cY
• progressive sensorineural hearing loss after age
10yr
• progressive glomerulonephritis leading to
endstage renal disease
• variable opthalmologic findings
• X-linked = 85% cases
• Also AR =15%
Mitochondrial syndromes
Mutation in MTRNT1 gene found in 2-6% of
patients with diabetes mellitus in Japan
 61% of people with diabetes and this
mutation have hearing loss
 Sensorineural
 develops only after onset of diabetes
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Non-syndromic Hearing loss
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At least 70% of hereditary deafness
No associated visible abnormalities of the
external ear nor any related medical
problems
66 genes known to cause NSHL
Can be associated with abnormalities of
middle and/or inner ear
Again AD (70-80%), AR (20-25%), XL (1-5%)
and Mitochondrial
Non-syndromic Hearing loss
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Gene loci for NSHL are designated DFN (for
DeaFNess)
• DFNA= Autosomal dominant
• DFNB= Autosomal recessive
• DFNX= X-linked
• The number after these designations reflects the
order they were mapped or discovered
Autosomal dominant NSHL
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Unlike AR NSHL, AD NSHL does not
have an identifiable single gene
responsible for the majority of cases
Audioprofiling can be distinctive in AD
NSHL and is useful in developing an
evaluation strategy for genetic testing
Autosomal recessive NSHL
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DFNB1 is caused by mutations in the GJB2
gene which codes for the protein ‘connexin
26’ and the GJB6 GENE which codes for
‘connexin 30’
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account for 50% of autosomal recessive
NSHL
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Approx 1 in 33 of general population are
carriers for GJB2
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the other 50% are attributed to numerous
other gene mutations ( up to DFNB84!)
X-linked NSHL
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DFNX3 characterised by mixed
conductive-sensorineural hearing loss
DFNX2 & DFNX4 cause profound
prelingual HL
DFNX6- high-frequency loss from 5-7
yrs progressing to severe to profound
HL by adulthood over all frequencies.
Mitochondrial NSHL
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Hearing loss can be induced in some
people who have mitochondrial
mutations by aminoglycoside use.
Molecular genetic testing
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Guided by presentation (phenotype)
For example, testing for GJB2 and GJB6 is usual for
congenital NSHL in the first instance then move to
others if negative
If CT scan shows dilated vestibular aqueduct pendrin
gene testing requested (University Iowa)
Until recently required multiple tests to determine
cause
Some centres now using multigene screening panels
–currently involves sending DNA overseas
University of Iowa offers OtoScope- tests for 66
genes
Genetic Evaluation and
Counselling
The goal of genetic evaluation and
counselling is to provide information and
support that can assist families in making
choices that are appropriate for them
Genetic Evaluation and
Counselling
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Correctly diagnosing the specific cause of
hearing loss can provide information on
prognosis and is essential for accurate
genetic counselling
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Many people do not know the exact cause of
their or their children’s deafness and could
benefit from genetic evaluation and
counselling to assist with health care and /or
family planning issues
Genetic Evaluation and
Counselling
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Family history
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3-4 generations
hearing status of parents and siblings
consanguinity
paternity
ethnicity/ country of origin
syndromic vs non-syndromic features
Genetic Evaluation and
Counselling
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Medical and perinatal history
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Intruterine infections
meningitis
ototoxic drugs
prenatal alcohol exposure
hypoxia/ jaundice
Clinical examination
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otologic examination
airways examination
documentation of any dysmorphic features
neurological examination
Genetic Evaluation and
Counselling
Audiometry testing and comparison of tests
from different family members
 Physical examination
 CT scans- to detect inner ear malformations
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GENETIC TESTING - if indicated
Genetic testing
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Detects changes associated with inherited
conditions:
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direct analysis of DNA or RNA (gene testing)
chromosome analysis (cytogenetics)
biochemical testing for protein products of genes
indirect testing of genetic markers (linkage)
Types:
• prenatal inc. pre-implantation genetic diagnosis
(PGD)
• newborn
• diagnostic
• predictive
• carrier screening
Genetic Counselling:
What is it and why is it important?
It is a process in which information and support
are provided to families who have or are at risk
for a variety of inherited or genetic conditions
including deafness, in order to assist them to
negotiate the difficult personal, family, cultural,
social and ethical issues that may arise.
Genetic Counselling
Sensitive and empathic gathering and sharing
of information and results of testing
 Working with families on issues of grief,
adjustment, acceptance of diagnosis
 Assisting with decision making based on the
information provided
 Emphasis on personal and family dynamics in
the context of genetic testing and diagnosis“Genetics is a Family Business”
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Counselling issues for Deaf families
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Deaf Culture
The use of skilled interpreters- not
family members
Terminology used:
• probability or chance vs risk
• deaf or hearing vs affected or unaffected
• deaf /hard of hearing vs hearing impaired
or handicapped
• Avoiding “abnormal”or “ disease causing”
when referring to genes
Counselling issues for Deaf families
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Knowledge of and experience of genetic
testing and genetic counselling
attitudes towards newborn and prenatal
genetic testing for deafness
Preference for a hearing or deaf child
Risks and benefits of genetic testing for
deafness
Counselling issues for Deaf families
Many deaf people are interested in
obtaining information about the cause of
their own deafness, including
information on medical, educational and
social services rather than just
information about prevention,
reproduction or family planning
Followup
Repeating genetic evaluation if no specific
diagnosis made initially or if test results or
new tests become available
 Evaluation of progressive hearing loss
 Other speciality directed examinations
according to patient need ( eg neurological,
cardiac, renal etc)
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CONCLUSIONS
The role of genetic counselling and genetic
testing will continue to expand
 New discoveries and technologies will will
increase the complexity of genetic testing
options
 Rapid developments highlight the importance
of recontacting families and ensuring families
maintain links with providers
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CONCLUSIONS
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There are currently limited numbers of
geneticists or genetic counsellors
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Therefore ALL professionals involved should
to familiarise themselves with current
discoveries and accepted protocols for
genetic testing and counselling
Mid North Coast LHD & HNE- LMNC
Genetic Counsellors
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Coffs Harbour:
• Karen Robinson,
• Coffs Harbour Health Campus
Ph: 6656 7806
• email: [email protected]
Port Macquarie:
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Ph: 65 882 783
Taree:
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Kim Frumar and Carol Sorensen
• Port Macquarie Health Centre
• email: [email protected]
Bruce Hopper
• Taree Community Health Centre
• email: [email protected]
Ph: 6592 9703
All other areas call : Centre for Genetic Education for contact details
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Ph: 9906 9599