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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 • • • • 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 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 IV:3 Aysha V:1 Genotyped Zahoor ahmad V:2 V:3 mukhtar ghulam Fatima IV:4 M.Din Charagh bibi(hajan) VI:6 VII:1 VII:2 Yasmeen Abdul Ghaffar VI:1 VI:2 VII:4 kalsoom Bashiran Imran VII:3 Genotyped M waqas VII:5 VII:6 M Iqbal VI:3 VI:4 V:4 V:5 Raj bibi M.Din 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 • • • • • 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