1. Genetic Counselling and Predictive testing for Huntingtons Disease Ruth Glew 18 November 2011 Understanding and managing Huntingtons Disease in a multidisciplinary Environment

2. Overview The genetics of HD The genetics of HD Role of genetics services Role of genetics services Predictive testing Predictive testing Prenatal diagnosis Prenatal diagnosis Family implications Family implications Who and how to refer Who and how to refer

3. Common myths HD affects only females/males HD affects only females/males HD skips generations HD skips generations If I am similar to my affected parent I am more likely to be affected If I am similar to my affected parent I am more likely to be affected If I have no symptoms by age 40yrs I will be OK If I have no symptoms by age 40yrs I will be OK

4. Inheritance

5. Autosomal dominant inheritance mother unaffected father affected 50:50 chance the child will inherit the disease from the father gene with alteration working copy of gene

6. 1 ttg ctg tgt gag gca gaa cct gcg ggg gca ggg gcg ggc tgg ttc cct ggc cag cca ttg 61 gca gag tcc gca ggc tag ggc tgt caa tca tgc tgg ccg gcg tgg ccc cgc ctc cgc cgg 121 cgc ggc ccc gcc tcc gcc ggc gca cgt ctg gga cgc aag gcg ccg tgg ggg ctg ccg gga 181 cgg gtc caa gat gga cgg ccg ctc agg ttc tgc ttt tac ctg cgg ccc aga gcc cca ttc 241 att gcc ccg gtg ctg agc ggc gcc gcg agt cgg ccc gag gcc tcc ggg gac tgc cgt gcc 301 ggg cgg gag acc gcc atg gcg acc ctg gaa aag ctg atg aag gcc ttc gag tcc ctc aag 361 tcc ttc cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag 421 cag cag cag caa cag ccg cca ccg ccg ccg ccg ccg ccg ccg cct cct cag ctt cct cag The Huntingtons Disease Gene

8. Age of onset Variable – average 30-50yrs Variable – average 30-50yrs Anticipation Anticipation Juvenile HD Juvenile HD HD in older age HD in older age

9. What is genetic counselling Genetic counselling is the process of helping people understand and adapt to the medical, psychological and familial implications of a genetic diagnosis. Genetic counselling is the process of helping people understand and adapt to the medical, psychological and familial implications of a genetic diagnosis. This process integrates the following: Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence. Education about inheritance, testing, management, prevention, resources and research. Counselling to promote informed choices and adaptation to the risk or condition. This process integrates the following: Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence. Education about inheritance, testing, management, prevention, resources and research. Counselling to promote informed choices and adaptation to the risk or condition.

10. Being at risk period of adjustment to risk period of adjustment to risk uncertainty uncertainty possible altered life plans possible altered life plans burden of care burden of care potential discrimination/stigma potential discrimination/stigma ANXIETY

11. Referrals 31yr man, mother died last year of HD. He is Schizophrenic ? related to substance misuse. He wants genetic counselling for himself and as regards his children. 31yr man, mother died last year of HD. He is Schizophrenic ? related to substance misuse. He wants genetic counselling for himself and as regards his children. 17 yr girl wants wheels put in motion for her to have test for HD. Mother has tested positive for the gene and grandmother is affected 17 yr girl wants wheels put in motion for her to have test for HD. Mother has tested positive for the gene and grandmother is affected 61 yr lady discovered brother diagnosed with HD. She is anxious for her own immediate family and extended members and is requesting screening 61 yr lady discovered brother diagnosed with HD. She is anxious for her own immediate family and extended members and is requesting screening 40yr lady known to have HD gene. She feels she has some abnormal movements and is having a difficult time with depression. 40yr lady known to have HD gene. She feels she has some abnormal movements and is having a difficult time with depression. 32yr lady had positive predictive test, is now pregnant and wants prenatal diagnosis 32yr lady had positive predictive test, is now pregnant and wants prenatal diagnosis 39yr man detained HMP mother died HD. He has past psychiatric history. Has had CT scan and needs to be seen for genetic testing as he is concerned about his future. 39yr man detained HMP mother died HD. He has past psychiatric history. Has had CT scan and needs to be seen for genetic testing as he is concerned about his future. 47yr man, mother has HD and he is aware of implications, he is unsure whether or not he should have formal testing. 47yr man, mother has HD and he is aware of implications, he is unsure whether or not he should have formal testing. 14yr boy, father had HD and committed suicide, he would like further information regarding the condition and possible testing. Hew lives with foster parents. 14yr boy, father had HD and committed suicide, he would like further information regarding the condition and possible testing. Hew lives with foster parents.

12. REFERRAL GENETIC COUNSELLOR CONTACT: family pedigree family experience of HD prior knowledge families questions GENETICS CLINIC APPOINTMENT: information risks options where to go from here TESTING Predictive/prenatal/diagnostic CONTINUED FOLLOW-UP annual H/V, clinic appt, tel contact

13. Predictive testing for HD

14. What is predictive testing? Common features: currently healthy currently healthy at risk of genetic condition at risk of genetic condition predicting the future predicting the future shortened life expectancy shortened life expectancy right not to know/to know right not to know/to know reproductive decision making reproductive decision making experience of previous generations experience of previous generations

15. Why is predictive testing taken so seriously? HD is at present untreatable HD is at present untreatable Having the altered gene means developing the disorder Having the altered gene means developing the disorder Loss of the get out clause Loss of the get out clause Long term effects: emotionally, socially & financially Long term effects: emotionally, socially & financially Risk of adverse reaction Risk of adverse reaction WFN/IHA guidelines 1994 – testing only in regional genetics centres Knowledge once given can never be taken away

16. Predictive testing protocol Minimum of 2 appointments Minimum of 2 appointments 2 months between each 2 months between each appointment appointment DNA sample at 2 nd appointment DNA sample at 2 nd appointment results available 4 weeks after appointment two results available 4 weeks after appointment two follow-up at 1 week, 1 month, then negotiated with patient follow-up at 1 week, 1 month, then negotiated with patient Appt 1 Appt 2 ? Follow-up Discharge -ve f/up cont + ve Appt +

17. Pre test discussion Confirm diagnosis Confirm diagnosis Rationale for testing Rationale for testing Experience of HD and risk Experience of HD and risk Benefits/disadvantages of testing Benefits/disadvantages of testing Implications – personal, family, social and financial (telling children) Implications – personal, family, social and financial (telling children) Plans for future/decisions resting on result Plans for future/decisions resting on result Coping skills/support network Coping skills/support network Supporters feelings Supporters feelings Coexisting stressors Coexisting stressors Explanation of outcomes/ examination/post test Explanation of outcomes/ examination/post test

18. Follow-up choices following P/S test No follow up at present No follow up at present Within Genetics HD clinic/district clinic/GC Within Genetics HD clinic/district clinic/GC Asymptomatic clinic (Anne Rosser) - assessment and research Asymptomatic clinic (Anne Rosser) - assessment and research

19. UK data

20. HD Pre-symptomatic Test Figures (1993 - 2010) Year - Number of tests

21. Pre-symptomatic tests - Age Distribution 1994 and 2010

22. HD Pre-symptomatic testing - Prior Risk (2010) 50% risk n = 358 50% risk n = 358 25% risk n = 23 25% risk n = 23 Other n = 19 Other n = 19

23. HD Pre-symptomatic testing - Sex Distribution (2010 ) 2010 2010 male 45% n= 179 female 55% n= 223 1993-2010 1993-2010 male 44% female 56%

24. HD Pre-symptomatic Testing - Outcome (2010) 2010 Exp = 223 Normal = 175 RP = 16 Int = 22 Exp/Int = 2

25. Reasons for testing 2010 A - decrease uncertainty A - decrease uncertainty B - plan future B - plan future C - family planning C - family planning D - possible therapy D - possible therapy E - inform family E - inform family F - other F - other

26. Other more challenging issues 25% risk 25% risk Testing of minors Testing of minors Mental health problems Mental health problems Learning difficulties Learning difficulties Difficult family dynamics Difficult family dynamics Individuals unaware of symptoms or in denial Individuals unaware of symptoms or in denial

27. Prenatal testing and Pre-implantation Genetic diagnosis (PGD) Prenatal testing at 11 or 15 weeks of pregnancy (15-20 tests a year UK) Prenatal testing at 11 or 15 weeks of pregnancy (15-20 tests a year UK) Only if couple wanting to end pregnancy if Only if couple wanting to end pregnancy if foetus affected foetus affected PGD - IVF technology to re-implant unaffected embryos PGD - IVF technology to re-implant unaffected embryos

28. Clinical Cases

29. Diag 20s P+ Case 1 DAWNTINAFFIONNATASHA SION JAMES 50+yrs

30. Case 2 BEN HAROLD LIAM P-

31. Diag 70yrs JILL 65yrs

32. REFERRAL INDIVIDUAL AT RISK ? DIAGNOSIS/ASYMP GENE CARRIER RESEARCHAFFECTED GC PRECLINIC CONTACT pedigree, consents and molecular confirmation DISTRICT GENETIC CLINIC MANAGEMENT CLINIC HD PREDICTIVE TEST CLINIC ASYMPTOMATIC GENE + CLINIC withdrawalresult REGULAR F/UP DISCHARGEREGULAR F/UP DISTRICT F/UP OPEN ACCESS HD Clinical Pathway

33. Who to refer? Individuals with a new diagnosis Individuals with a new diagnosis –How to tell the family? –How to tell the children? Individuals at risk Individuals at risk –Those who want more information about HD and/or their options –Those who want a test –Those who dont want to risk passing it on –Those who are symptomatic, but in denial

34. Referrals to: Professor A Clarke. Department of Medical Genetics University Hospital of Wales Heath Park Cardiff CF14 4XW Tel 02920 742577