Transcript Update on genetics research on stuttering

Update on genetics research
Dennis Drayna, PhD
NIDCD/National Institutes of Health
US Public Health Service, DHHS
Who are we?
• National Institute on Deafness and
Other Communication Disorders
• National Institutes of Health
• U.S. Public Health Services
• U.S. Department of Health and Human
Services
• Your tax dollars at work
Fact #1- Not all stuttering is
genetic
• Of the people who come to stuttering
therapy, about half report a family
history and half have no family history
• So, perhaps half of stuttering is due to
genetic factors
• The other half is due to unknown
causes
– Low birth weight, perinatal hypoxia
Fact #2 - Genes do not entirely
control stuttering in anyone
• Severity varies from day to day, and in
children, from month to month
• Stuttering therapy can largely eliminate
stuttering
– Their genes have not changed
The power of genetics
• If a disorder is genetic in origin, we can
find the gene that causes the disorder
• Once we have the gene, we can see
what the gene codes for, and what the
gene product does, both normally and in
individuals who stutter
• Can lead us to the cells and molecules
involved in the disorder
Genetics is great, but…
• How do we know stuttering has
anything to do with genetics?
• Nature vs. nurture
Evidence for genetic factors in
stuttering
• Twin studies
– Identical twins always more alike regarding stuttering than
fraternal twins
• Adoption studies
– Adopted children raised by stuttering parents do not stutter any
more than children in the general population
• Family clusters of stuttering
– Several large families have been described that have many,
often distantly related members who stutter
• Segregation analysis
– Stuttering does not generally occur in families like a simple
inherited trait
NIH genetics research
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Genetic linkage studies
Performed in families
Applicable to any inherited disorder
Identify the location of the gene or
genes that cause the disorder
Focus
• Persistent stuttering
• Family history of stuttering
NIH linkage studies
• North American families
– Not very enlightening
• West African families
• Pakistani families
Cameroon, West Africa
• Initial contact came through the online
symposium sponsored by Stuttering
Home Page
• Query from individual in Cameroon
• Initial information difficult to interpret
– Subsequent exam at the N.I.H. Clinical
Center showed no medical abnormalities
except stuttering
Linkage studies – Cameroon
Cameroon Family 1
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Cameroon linkage
The long march
• Did one survey and found a signal on
chromosome 1
– Did not replicate
• Did two additional surveys, using two
different methods
– Took ~ 2 years of work
• Found clear signal on chromosome 15
Cameroon linkage
• Linkage on chromosome 15 still has
puzzling aspects
• There’s likely to be more than one
variant gene at this location at work in
this family
• Don’t yet know what this gene is
Linkage studies - Pakistan
Pakistani stuttering families
PKST 072
I:1
II:1
I:2
II:2
II:3
II:4
III:1
III:2
III:3
III:4
III:5
III:6
III:7
Sooban
M.Din
Bibi Rani
Nizam Din
Ali Muhammad
Bagh Bare
Roshan Din
IV:1
IV:2
Aysha
V:1
Genotyped
Zahoor ahmad
V:2
IV:3
IV:4
M.Din
Charagh bibi(hajan)
V:3
mukhtar
VII:1
VII:2
Abdul Ghaffar
VI:1
VI:2
VII:4
kalsoom
Bashiran
Imran
VII:3
Genotyped
M waqas
VII:5
V:5
M.Din
ghulam Fatima
VI:6
Yasmeen
V:4
Raj bibi
VII:6
M Iqbal
VI:3
VI:4
VI:7
VI:8
Haneef haji Tufail haji yousaf
VII:19
VII:7
VII:8
VII:18
VII:17
Abdul Jabbar
Bushra
Sohail
Akram Surriya
VII:9
VII:10 VII:11
Aslam
VII:12
Ilyas
VII:20
VIII:2
VIII:3
IX:18
Atif
IX:2
Tahir
X:14 X:12
X:13
X:15
X:1
Genotyped
Abid
IX:3
IX:4
IX:5
Genotyped
Firdos Shagufta Tashfeen
IX:6
Genotyped
Kashif
IX:7
Genotyped
Yaseen
IX:8
Genotyped
Zulfiqar Ali
IX:9
Genotyped
M Tayyab
VII:13
VIII:6
Asad
IX:10
IX:11
robina
awais
IX:12
Genotyped
M Hussain
IX:13
IX:14
shahid
hafeez
IX:15
IX:16
shazia Yasmeen
IX:17
Nazia
X:16
X:2
Genotyped
Haroon
X:3
Genotyped
Asif
X:4
X:5
X:6
shan
Iqra
Tayyaba
PKST 72
VI:10
VII:14
VII:15
VII:16
Rukhsana
Jameel
VIII:7
Asif
VIII:4
Usman
IX:1
VI:9
VII:21 VII:22 VII:23
Reehana shafeeq
VIII:5
VIII:1
VI:11
Amanat Rasheedan
VI:5
X:7
X:8
X:9
X:10
X:11
Amir
Ahmad
Fehmeeda
Jawwad
Hamza
Abdul Baree
Pakistan project
• Enrolled and analyzed 44 families
• Found strong evidence for linkage on
chromosome 12
• This region contains 87 genes
• Analyzed these genes in:
– Family PKST 72
– Other Pakistani stuttering families
– 96 unrelated Pakistanis who stutterer
– 96 unrelated normally fluent Pakistanis
New Results
• In review at a major scientific journal
– Nothing is true until the reviewers and
editors at the journal say it’s true
• All information strictly embargoed prior
to publication
Results of gene analysis
• Found mutation that went along with stuttering in
family PKST 72
• Same mutation in the same gene is present in
affected members (but not in normal members) of 3
other Pakistani stuttering families
• Same mutation in the same gene is observed in
several unrelated Pakistani individuals who stutter
• Same mutation was observed in a single affected
individual of Indian descent in the U.S.
• This mutation was not observed in normally fluent
individuals
Chromosome 12 gene analysis
• Examined the entire gene in:
– 96 unrelated Pakistani affected individuals
– 270 unrelated North American affected individuals
– 96 unrelated normally fluent Pakistanis
– 265 unrelated normally fluent North Americans
– All have a family history of stuttering
• Found several other mutations in this gene that occur
in individuals who stutter but do not occur in normally
fluent individuals
Looking beyond chromosome 12
• The chromosome 12 gene is part of a
well-known process within the body
– A metabolic pathway
• Other parts of this process are carried
out by the products of other well-known
genes
Examining other genes
• Found a number of mutations in each of
two other genes
• These mutations were found in multiple
individuals who stutter
• These mutations were not found in
normally fluent individuals
How common?
• Together, the mutations we’ve found in
these three genes appear to account for
5-10% of familial stuttering
• This amounts to 50,000 to 100,000
individuals in the U.S.
• Mutations in these genes probably
account for many more individuals who
stutter worldwide
What’s next?
• These genes provide an exciting
possibility for therapy in this group of
individuals
– Replace what’s missing
– Personalized medicine
• Making a new drug takes many years
and many hundreds of millions of
dollars
– Can’t expect a cure next week
What about the other 90%?
• Studies have shown that genetics works
• Enrolled a new group of Pakistani stuttering
families, each of which is large enough to be
useful for a linkage study on its own
• Chromosome 12 has already been ruled out
in these families
– Likely to find other places containing stuttering
genes
• Chromosome 15 will hopefully identify
another new gene
Current conclusions
• Studies have shown that genetics works
• There’s good hope for finding other
genes that cause stuttering, leading to
additional insights
• At least some stuttering is clearly in the
realm of clinical medicine
Acknowledgments
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NIDCD
– Changsoo Kang
– M. Hashim Raza
– Naveeda Riaz
– Eduardo Sainz
– Joe Kleinman
NISC/NHGRI
– Alice Young
– Jim Mullikan
NCBI
– Alejandro Schaffer
Hollins Communications
Research Institute
– Jennifer Mundorff
University of Chicago
– Stacy Steinberg
– Anna Pluzhnikov
– Nancy Cox
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CEMB/University of the Punjab
– Jamil Ahmad
– Shahid Khan
– S. Riazuddin
Stuttering Foundation of
America
British Stammering Association
National Stuttering Association
Speak Clear Association of
Cameroon
– Joseph Lukong
• Stuttering research
subjects worldwide
How do we make progress?
• You can help!
• Enrolling research subjects here today,
immediately following this workshop
• Compensation provided
What’s needed?
• Family history of stuttering
• Provide a small blood sample, taken
from your arm
• Understand and agree to the risks
involved
• Provide a Social Security number to
receive your compensation
– $25