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Discovery of Causes of Stuttering

Slideshow of presentation given by Dennis Drayna, Ph.D., to the National Stuttering Association on July 8, 2010.

You can download the slideshow in Microsoft PowerPoint format (656 KB) or play it right inside your Web browser.

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Dennis Drayna, Ph.D.
NIDCD/National Institutes of Health
US Public Health Service, DHHS

Evidence for genetic factors in stuttering

Research plan

North American linkage study

Citation for North American linkage study: Results of a Genome-Wide Linkage Scan for Stuttering. By Shugart YY, Mundorff J, Kilshaw J, Doheny K, Doan B, Wanyee J, Green ED, and Drayna D. In American Journal of Medical Genetics, volume 124A, pages 133 through 135. Published 2004.

Similar results from studies by others

Solution?
Specialized populations

Advantageous population structure—Pakistan

Finding stuttering families in Pakistan

Pakistani stuttering families

Text description follows.

Pedigree and Distribution of GNPTAB Glu1200Lys Mutation in Family PKST72

Genotype Number of Unaffected Subjects Number of Affected Subjects
GG (Glu/Glu) 4 3
Ga (Glu/Lys) 9 13
aa (Lys/Lys) 2 12

This slide shows the family tree of the largest Pakistani stuttering family we studied, designated PKST72. Subjects 77 and 89 (green ovals) were homozygous for the mutation but were unaffected, suggesting nonpenetrance. Subjects 65, 69, and 83 (pink ovals) were affected but differed from the other affected subjects with respect to the haplotype surrounding the gene for the alpha and beta subunits of N-acetylglucosamine-a-phosphate transferase (GNPTAB). Double lines indicate consanguineous unions. Squares denote male family members, circles female members, solid symbols affected members, and slashes deceased members.

Report Linking Chromosome 12 to Stuttering

Citation: Genomewide Significant Linkage to Stuttering on Chromosome 12. By Riaz N, Steinberg S, Ahmad J, Pluzhnikov A, Riazuddin S, Cox NJ, Drayna D. In American Journal of Human Genetics, volume 76, pages 647 through 651. Published 2005

Gene identification strategy

Variant of interest

Mutation associated with stuttering in family PKST72

Three other mutations in GNPTAB identified

GNPTAB

GNPTG

GNPTAB/G

NAGPA

The uncovering enzyme

GNPTAB/G mutations in known disorders

NAGPA mutations?

Discussion

Is stuttering a mild form of mucolipidosis?

Implications for Speech Language Pathology

How does a disorder of cell metabolism lead to stuttering?

Working hypothesis

Can we explain stuttering in more individuals?

Newly found Pakistani stuttering families

Text description follows.

This slide shows the family tree of a new stuttering family we've identified in Pakistan, designated PKST77. The circles represent females, the squares represent males. Filled-in (black) squares and circles represent people who stutter. Lines connecting males and females represent matings, with the offspring of those matings connected by lines beneath. Double lines indicate matings between people who are related to each other. The orange bars indicate individuals that we've obtained DNA samples from in this family.

Linkage analysis in PKST77

Text description follows.

This represents a plot showing the results of our genome-wide linkage scan in family PKST77. The vertical black lines represent scores that measure our evidence for linkage at markers down the length of each chromosome. The horizontal axis shows the position of each marker we tested, starting with the markers on chromosome 1 (the longest chromosome) on the left, and proceeding to chromosome 22 (the smallest chromosome) on the right. The large peak on chromosome 3 indicates that a gene at this locus is strongly linked to stuttering.

Acknowledgements

  • NIDCD
    • Changsoo Kang
    • M. Hashim Raza
    • Naveeda Riaz
    • Eduardo Sainz
    • Joe Kleinman
    • Alison Fedyna
  • NHGRI/NISC
    • Alice Young
    • Jim Mullikan
    • Donna Krasnewich
  • NIH Clinical Center
    • Penelope Friedman
  • NCBI
    • Alejandro Schaffer
  • Hollins Communications Research Institute
    • Jennifer Mundorff
  • 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

Research volunteers needed!

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