Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy.

1. Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford

2. Overview • Hypertrophic Cardiomyopathy • Clinical features • Genetics • Clinical sensitivity in our cohort • Factors affecting clinical sensitivity

3. Hypertrophic cardiomyopathy • Characterised by thickening of the heart muscle, most commonly of the left ventricle, with no obvious cause (e.g. high blood pressure, athletes heart) • Autosomal Dominant • Prevalence of 1/500 • Most common cause of heart related sudden death in people under 35 and athletes

4. The hypertrophic heart

5. Clinical Features • Clinically heterogeneous -No symptoms -Shortness of breath -Chest pain -Fainting -Dizziness -Palpitations -Exercise intolerance -Sudden death • Variable presentation, age of onset and clinical course • Differential diagnoses: -Cardiac amyloidosis -Hypertensive heart disease -Aortic stenosis -Athletes heart -Metabolic disease (Fabry’s disease, Danon disease) -Mitochondrial myopathy

6. Benefits of Genetic Diagnosis • Confirm clinical diagnosis/familial disorder • Offer testing to at risk family members to enable early diagnosis and treatment • Future • Risk stratification and prognosis • Patient management

7. Genetics • >20 genes known to be associated • Majority of genes encode components of the sarcomere (contractile apparatus of the heart) • Four genes commonly associated sarcomeric genes account for ~80% of mutations. • Double/compound variants reported in 5-10%

8. Cardiac muscle cell & sarcomere

10. Commonly associated sarcomeric genes

11. Clinical Sensitivity in HCM • HCM service introduced 2003 • Gene dossier submitted 2006 • Clinical sensitivity estimated to be 60% • Review clinical sensitivity in cohort (2003-2008) • Determine clinical sensitivity in our cohort (>700 probands) • Comparison with published data • Identify factors affecting clinical sensitivity

12. Clinical Sensitivity in our cohort • 737 probands screened • 346/737 variant detected • Clinical sensitivity 47%

13. Comparison with published data • Yield ranged from 13-61% • 8 most commonly associated genes ~47% • MYBPC3,MYH7,TNNT2,TNNI3 ~44% • ~3% increased sensitivity~30% more workload • 62% family history vs. 29% sporadic Van Driest et al Mayo Clin Proc 2005

14. Factors affecting clinical sensitivity Clinical Diagnosis Clinical sensitivity Analysis Strategy Results interpretation

15. Clinical Diagnosis • Exclusion of phenocopies • Family History • The future • Refining clinical criteria of “sarcomeric HCM” • Define frequency of phenocopies in HCM cohorts • Cost of clinical vs. genetic investigations

16. Analysis strategy • Analysis of less commonly associated genes • Assay sensitivity and specificity • New technology (Roche 454) • Expansion of screen • Faster throughput • Results interpretation • Cost implications

17. Interpretation of results

18. Issues with results interpretation-the usual suspects…….. • High number of private missense mutations • Functional domains of proteins not defined • Limited functional studies • Segregation studies confounded by: • clinical heterogeneity • variable penetrance & age of onset • SCD of other affected FMs • No clinically normal control cohort

19. Clinical sensitivity based on likely pathogenicity • All 47% • Highly likely & Likely 37% • Highly likely only 27%

20. In summary • Clinical sensitivity in our cohort 47% • Several factors thought to impact clinical sensitivity: • Clinical criteria for testing • Analysis strategy chosen • Results interpretation • Introducing new technology (Roche 454) and techniques (MLPA) to ensure comprehensive analysis • Hope that future studies will refine clinical criteria and overcome some of the issues with results interpretation

21. Acknowledgements Oxford SCD Team Dr Anneke Seller Karen McGuire Melanie Proven Omer Mohammed Jessica Thistleton Ria Hipkiss John Taylor Sarah Reid Penny Clouston NHS Department of Clinical Genetics Dr E. Blair