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Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford Overview • Hypertrophic Cardiomyopathy – Clinical features – Genetics • Clinical sensitivity in our cohort • Factors affecting clinical sensitivity 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 The hypertrophic heart 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 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 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% Cardiac muscle cell & sarcomere Commonly associated sarcomeric genes Gene Protein % of HCM MYH7 MYBPC3 TNNT2 TNNI3 TPM1 Beta Myosin heavy chain 25-35% Myosin-binding protein C 20-30% Troponin T 3-5% Troponin I <5% Tropomyosin 1 alpha <2% MYL3 MYL2 ACTC1 Regulatory myosin light chain <1% Essential myosin light chain Rare Actin Rare 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 Clinical Sensitivity in our cohort • 737 probands screened • 346/737 variant detected • Clinical sensitivity 47% 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 Factors affecting clinical sensitivity Clinical Diagnosis Analysis Strategy Results interpretation Clinical sensitivity 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 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 Interpretation of results Classification Family testing Highly likely /certain to be pathogenic. Testing available for unaffected family members (FMs). Likely to be pathogenic but cannot be formally proven. Recommend testing affected FMs prior to analysis of unaffected FMs. Intermediate-not possible to determine neutral/pathogenic. Recommend testing affected FMs. Testing unaffected FMs not indicated. Unlikely to be pathogenic but cannot be formally proven. Testing FMs not indicated. Neutral polymorphism -certainly not pathogenic. Testing FMs not indicated. 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 Clinical sensitivity based on likely pathogenicity Intermediate 21% Likely 21% Highly Likely 58% • All 47% • Highly likely & Likely 37% • Highly likely only 27% 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 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