Prevalence, Penetrance, and Phenotypic Expression of Cardiomyopathy-Associated Genetic Variants in a Quaternary Medical Center-based Biobank
Clinical Genetics and Therapeutics
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Primary Categories:
- Population Genetics
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Secondary Categories:
- Population Genetics
Introduction:
Cardiomyopathies (CM) are a leading cause of heart failure. Identification of genetic risk preemptively may allow detection of the earliest phenotypic manifestations through implementation of interval-based cardiac screening. Previous population-based genetic screening studies have inadequate phenotyping and limited follow-up.
Methods:
We analyzed 52,863 patients from a quaternary medical center-based biobank cohort for reportable variants in 22-cardiomyopathy genes. Prioritization of genetic variants was performed using Semi-Automated Variant Interpretation, a novel software that has been previously developed and validated at our center. Prioritized variants were then manually curated by at least 2 independent variant interpretation specialists. Clinical phenotypes and outcomes of participants with likely pathogenic/pathogenic (LP/P) variants were determined.
Results:
LP/P cardiomyopathy variants were present in ~ 1% of our cohort (n=427) within the following genes: BAG3 (n=3), DES (n=1), DSG2 (n=4), DSP (n=36), FLNC (n=20), LMNA (n=9), MYBPC3 (n=123), MYH7 (n=67), MYL2 (n=2), MYL3 (n=1), PKP2 (n=45), RBM20 (n=1), TNNC1 (n=1), TNNI3 (n=18), TNNT2 (n=5), TPM1 (n=3), TTN (n=101). A definitive disease penetrance defined as heart failure or cardiomyopathy was found in 34% (n=145) of genotype positive (G+) individuals. Possible disease penetrance defined as presence of structural heart disease identified by echocardiography was found in an additional 16% (n=68) of participants (e.g., concentric left ventricular hypertrophy, diastolic dysfunction, biatrial or left/right atrial enlargement). Combined definitive and possible disease penetrance was found in 50% (n=213) of G+ individuals. Arrhythmias and/or cardiac conduction disease (e.g., atrial fibrillation, atrioventricular block, ventricular arrhythmia) were present in 41% (n=176) of G+ individuals .
Conclusion:
Cardiomyopathy associated LP/P variants are present in a small subset of a large quaternary medical center population as previously reported but unlike prior studies, disease penetrance manifesting as cardiac structural abnormalities and heart failure is high in G+ individuals.
Cardiomyopathies (CM) are a leading cause of heart failure. Identification of genetic risk preemptively may allow detection of the earliest phenotypic manifestations through implementation of interval-based cardiac screening. Previous population-based genetic screening studies have inadequate phenotyping and limited follow-up.
Methods:
We analyzed 52,863 patients from a quaternary medical center-based biobank cohort for reportable variants in 22-cardiomyopathy genes. Prioritization of genetic variants was performed using Semi-Automated Variant Interpretation, a novel software that has been previously developed and validated at our center. Prioritized variants were then manually curated by at least 2 independent variant interpretation specialists. Clinical phenotypes and outcomes of participants with likely pathogenic/pathogenic (LP/P) variants were determined.
Results:
LP/P cardiomyopathy variants were present in ~ 1% of our cohort (n=427) within the following genes: BAG3 (n=3), DES (n=1), DSG2 (n=4), DSP (n=36), FLNC (n=20), LMNA (n=9), MYBPC3 (n=123), MYH7 (n=67), MYL2 (n=2), MYL3 (n=1), PKP2 (n=45), RBM20 (n=1), TNNC1 (n=1), TNNI3 (n=18), TNNT2 (n=5), TPM1 (n=3), TTN (n=101). A definitive disease penetrance defined as heart failure or cardiomyopathy was found in 34% (n=145) of genotype positive (G+) individuals. Possible disease penetrance defined as presence of structural heart disease identified by echocardiography was found in an additional 16% (n=68) of participants (e.g., concentric left ventricular hypertrophy, diastolic dysfunction, biatrial or left/right atrial enlargement). Combined definitive and possible disease penetrance was found in 50% (n=213) of G+ individuals. Arrhythmias and/or cardiac conduction disease (e.g., atrial fibrillation, atrioventricular block, ventricular arrhythmia) were present in 41% (n=176) of G+ individuals .
Conclusion:
Cardiomyopathy associated LP/P variants are present in a small subset of a large quaternary medical center population as previously reported but unlike prior studies, disease penetrance manifesting as cardiac structural abnormalities and heart failure is high in G+ individuals.
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