Download (HCM) - Katie Thomson - Association for Clinical Genetic Science

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