1. What Is In Your Genes? Anna Frangulov, B.S. Research Coordinator Children’s Hospital Boston

3. Why Hearing Loss is So Common?

4. Structure of the Ear

5. Sound wave Hair Cell the Cochlea “snail” Extensions Hair Cell

6. Structure of the Ear Conductive HL Sensorineural HL

7. Genetic Infections Drug-Related Structural What Causes Hearing Loss? Unknown Traumas/ Exposures Non-Genetic

8. How Genetic HL occurs?

9. Chromosomes in Nucleus 23 Pairs of Chromosomes MOM DAD

10. One Chromosome Pair Genes “instruction manual”

11. Genes

12. Chromosome Pair Genes Mutation “error”

13. How Is Mutation Passed On (Inherited)?  Recessive ~80%  Dominant ~15%  X-Linked ~2%  Mitochondrial >2%

14. Dominant Inheritance Mutation “error" Hearing Hearing Loss Hearing

15. Point #1 The risk rate is for every child

16. Carrier Mutation “error" Hearing

17. How a Recessive Mutation is Passed? Carrier –No Hearing Loss Affected Child— Hearing Loss

18. Recessive Inheritance Hearing Loss Hearing

19. Point #2 Most children with genetic cause of hearing loss are born to parents with normal hearing

20. Sex Chromosomes Hearing Hearing Loss

21. X-Linked Inheritance HL

22. Mitochondrial Inheritance Hearing Loss

23. Every child has 50% Every child has 25% Dominant Inheritance Recessive Inheritance Hearing Loss Hearing “Carrier”

24. X-Linked Mitochondrial Mutation is on X chromosome All males have 50% All children w/HL Mother

25. HOW? WHO? WHY?

26. HOW Do We Know if HL is Genetic?

28. WHO Should Have a Genetic Test?  Case A: Syphilis  Case B: CMV  Case C: Prematurity  Case D: High bilirubin level Everybody with Sensorineural HL Also 2 Mutations in Cx26!!

29. Point #3 Even if you know your cause for hearing loss, you may also have an underlying genetic cause

30. WHY Should We Have a Genetic Test??

31. Benefits  a definite cause  family members realize that they are carriers & determine risk factors for future children  helps to find appropriate treatment/ management

32.  does not necessarily find the answer  severity of HL may not be predicted  a person may have mutations, but not have HL Limitations

33. Things to Consider Things to Consider  Primary Care/ Pediatrician  ENT  Audiologist Clinical Geneticist  Clinical Geneticist  Genetic Counselor  Clinical Molecular Geneticist 1.Talk to knowledgeable professional

34. Things to Consider 3. Cost 2. What tests are done?  Cx26  Cx30  Mitochondrial Tests  Pendred

35. UNDERSTANDING TEST RESULTS (example Cx26)

36. What Does the Result Mean?  Two Mutations are Found  No Mutations are Found  Mutations w/Unknown Significance  One Mutation is Found ?? ~10% ~70% ~18% ~1%

37. One Mutation Found  Mutation unrelated to deafness  Test did not find 2 nd mutation  Dominant mutation  There may be a mutation in another gene

38. Future in Genetics and HL  More Genetic Tests GeneChip Technology Deafness GeneChip (Rehm Study): MYO7A, OTOF, MYO6, USH1C, PRES, TMPRSS3, TMIE, GJB2 Deafness GeneChip (Greinwald Study): MYO7A, OTOF, CHDH23, KCNE1, KCNQ1, PDS, GJB6, GJB2 Two GeneChips are available right now:

39. Things to Remember  Most children with HL are born to parents with normal hearing  The risks rates is for every child  If you have other cause for hearing loss you may also have an underlying genetic cause  A negative genetic test result = inconclusive

40. Questions?

41. Research Studies  Connexin 26 Study- individuals with Cx26 mutations  Genetic Testing and Counseling Study - If you or your child has had genetic testing for hearing loss and you are willing to fill out a questionnaire  GeneChip Study - individuals with hearing loss who and parents with normal hearing  Novel Gene Discovery Study - five or more family members with hearing loss

42. Also in Spanish! Educational Materials http://hearing.harvard.edu

43. Helpful Information  Genetic Counselor - Rebecca Madore call 617-355-4534 to set an appointment or email rmadore@partners.org rmadore@partners.org  Department of Clinical Genetics – To make appointment with Clinical Geneticist call 617-355-6394.  National Society of Genetic Counselors (NSGC) www.nsgc.org www.nsgc.orgwww.nsgc.org  Help us evaluate educational material  Research Study Participation & Booklets Orders: Anna Frangulov 617-515-2962 or anna.frangulov@childrens.harvard.edu 617-515-2962 or anna.frangulov@childrens.harvard.edu