Update on genetics research

Dennis Drayna, PhDNIDCD/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

• 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

.

Cameroon linkageThe 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 familiesPKST 072

VII:23

IV:2

VI:3Haneef

VI:5haji yousaf

VI:4haji Tufail

VI:2Bashiran

VI:1kalsoom

V:3ghulam Fatima

IX:14hafeez

IX:11awais

IX:12GenotypedM HussainIX:13shahid

V:1GenotypedZahoor ahmad

IX:9GenotypedM TayyabIX:8GenotypedZulfiqar Ali

IX:5GenotypedTashfeenIX:7GenotypedYaseen

IX:6GenotypedKashif

III:2M.Din

III:1Sooban

VII:5M Iqbal

VII:3GenotypedM waqasVII:2

Abdul Ghaffar

X:3GenotypedAsif X:2GenotypedHaroon

X:1GenotypedAbid

IX:10robina

IX:15shazia

X:5Iqra

VII:4Imran

V:2mukhtar

X:4shan

VII:7Abdul Jabbar

VII:6

VIII:3Usman

VIII:2VIII:1 VIII:4

IX:3Firdos

IX:4Shagufta

IX:2Tahir

IX:1Atif

X:6 Tayyaba

IX:16Yasmeen

IX:17Nazia

VII:1Yasmeen

VII:8Bushra

X:8Ahmad

X:7Amir

X:9Fehmeeda

X:10Jawwad

X:11Hamza

IV:1Aysha

III:4Nizam Din

III:3Bibi Rani

II:2II:1

III:5Ali Muhammad

III:6Bagh Bare

II:3 II:4

I:1 I:2

III:7Roshan Din

IV:3M.Din

IV:4Charagh bibi(hajan)

VI:6Amanat

VI:7Rasheedan

VII:12VII:10Aslam

VII:11Ilyas

VII:13Reehana

VII:15Rukhsana

VII:9Surriya

VIII:5Asif

VII:14shafeeq

VIII:6Asad

VII:16Jameel

VIII:7Abdul Baree

V:5M.Din

V:4Raj bibi

IX:18

X:12X:13X:14

VII:17Akram

VII:18Sohail

VI:8 VI:9VI:10VI:11

VII:19VII:20VII:21VII:22

X:15X:16

PKST 72

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• 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

• 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