clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy
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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. - PowerPoint PPT PresentationTRANSCRIPT
Clinical sensitivity of molecular genetic testing
in hypertrophic cardiomyopathy.
Kate ThomsonMolecular Genetics Laboratory,
Oxford
Overview
• Hypertrophic Cardiomyopathy– Clinical features– Genetics
• Clinical sensitivity in our cohort
• Factors affecting clinical sensitivity
• 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
Hypertrophic cardiomyopathy
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
Gene Protein % of HCM
MYH7 Beta Myosin heavy chain 25-35%
MYBPC3 Myosin-binding protein C 20-30%
TNNT2 Troponin T 3-5%
TNNI3 Troponin I <5%
TPM1 Tropomyosin 1 alpha <2%
MYL3 Regulatory myosin light chain <1%
MYL2 Essential myosin light chain Rare
ACTC1 Actin Rare
Commonly associated sarcomeric genes
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 sensitivity
ClinicalDiagnosis
AnalysisStrategy
Results interpretation
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 resultsClassification Family testingHighly likely /certain to be pathogenic. Testing available for unaffected family
members (FMs).
Likely to be pathogenic butcannot be formally proven.
Recommend testing affected FMsprior to analysis of unaffected FMs.
Intermediate-not possible todetermine neutral/pathogenic.
Recommend testing affected FMs. Testing unaffected FMs not indicated.
Unlikely to be pathogenic butcannot 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
• All 47%• Highly likely & Likely 37%• Highly likely only 27%
Intermediate21%
Likely21%
Highly Likely58%
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 TeamDr Anneke SellerKaren McGuireMelanie ProvenOmer MohammedJessica ThistletonRia HipkissJohn TaylorSarah ReidPenny Clouston
NHS Department of Clinical GeneticsDr E. Blair