Clinical Genetics TRAGADY

1. Clinical GeneticsTRAGADY

2. Cardiac Genetics Clinic (Adult) Queensland • Awareness of improved testing • Need for formalised family follow up • Developed combined clinic from Feb 07 • Clinical genetics and cardiology

3. Hypertrophic cardiomyopathy • Autosomal dominant • 1 in 500 • Commonest cause of sudden cardiac death in individuals <35years • Mutations identified in 11 genes, mostly encoding sarcomere proteins

4. Testing issues • Many genes, many mutations • Availability • Cost • More than one mutation • Consent • ELSI • Children

5. Testing • 10 genes screened • Family history: 60% chance finding mutation • No family history: 30% chance

6. Availability • Not currently in Australasia • Long QT being developed • Main centre = Denmark

7. Cost of screening • On basis of guidelines, if screen from 10-60 years in 4 at risk family members • Minimal costs for clinical assessment, echo and ECG = about $30000 • To test 4 at risk relatives if mutation known = $1000 • PhD ongoing looking at Health Economic Analysis of Cardiac Genetic Diseases in Australia (including Quality of Life data)

8. More than one mutation • Number of studies shown people with 2 mutations in same gene or different genes • Interpretation difficult within families • Could be related to clinical course ie may be more severe

9. Consent • Need to explain limitations of testing • Possibility of 2 mutations and family studies necessary • Be aware of consequences ie if asymptomatic will be then be considered “affected” • Screening/ interventions possible

10. Children • Not able to give informed consent • Issues of confidentiality • Pros v cons • Discrimination • Loss of opportunity • When to test • Why?

11. Testing children • Is there any medical benefit? • Undertake regular cardiological examination in all children who are first degree relatives • 11-20y: annually • until hypertrophy appears or until the child reaches the age and maturity to make his/her decision • genetic testing may be performed in selected cases eg child in competitive sports

12. Development of protocols • Determine reasonable age clinically • Use team approach involving child psychiatry • Have some justifiable flexibility • Individual approach

13. Future developments • Ongoing development Australasian guidelines • Consider funding and develop testing for more conditions with appropriate interpretation • Collaboration and research; CIDG, TRAGADY

14. Sudden unexplained death • Up to 400000 deaths US/year • Mostly cardiac disorders • >40 y coronary artery disease most prevalent cause • Younger; PM indicate 60-75% have potentially inherited diseases • In clinical practice, many remain unexplained

15. Surviving relatives • Family members of 43 SUD • 183 surviving relatives • Familial disease identified in 17 families (40%) on clinical evaluation • Clinical evaluation useful in family members

16. Surviving relatives • 12 involved primary electrical disease • Mutations in 10 families • Finding the diagnosis more likely when more relatives were examined, more family members affected

17. Role of Molecular Genetics • Very useful • In those where no cause identified on PM, may make the diagnosis • May confirm the diagnosis where equivocal • May confirm the diagnosis • Important to accurately identify affected family members

18. Potential problems in clinical screening alone • How many relatives need to be/are screened? • How long for? • If no-one clearly affected on screening, what does it mean for rest of family? • Who to DNA test if no-one apparently clinically affected? • Would numerous relatives be tested? • If test 5 and no mutation, is an inherited condition ruled out?

19. Usual Practice in Molecular Testing • Test an affected individual • Higher likelihood of abnormality • May be a new mutation • Even if not, only 50% relatives may carry it; if clinically unaffected who to test? • In these families, affected individual presents dead

20. ?Arrhythmia 3y 5y Extended family normal clinically No confirmed diagnosis in parent Unknown risk for children; too young to test in own right

21. SUD 34y male ?VF Couple of “faints” Numerous cardiac investigations and follow up No sample available for testing from brother ?? Access and consent Continued uncertainty

22. HCM family ? Due for ICD; Would lose job Estranged

23. ICD No mutation, no ICD Mutation found

24. HCM 42y 12y 16y Not clinically affected; is it because no mutation or unaffected? Need significant screening Need mutation analysis in proband

25. Family assessment • May need to screen many times over a number of years • Clinical screening not always able to detect mutation carriers • Affected proband best to test; we know they are affected • If proband dead, unable to access samples and obtain consent

26. Coroners Act (Queensland) Section 3. 3 • d) help to prevent deaths from similar causes happening in the future by allowing coroners at inquests to comment on matters connected with deaths, including matters related to- • (i) public health or safety; or (ii) the administration of justice.

27. Ideal • Molecular testing samples taken by forensic pathologist to enable molecular determination/confirmation cause of death in conjunction with; • Possibility/confirmation of inherited condition raised with family and detailed family history to inform any potential testing • Family referred to cardiac genetics clinic • Screening clinical and/or genetic testing carried out