Genetic testing can establish a definitive, etiologically-based diagnosis for inherited cardiovascular diseases. Playing a vital role in early identification and treatment, it can save the lives of the patient and at-risk family members. Two studies at the National Heart Centre Singapore have led to a better understanding of inherited cardiovascular diseases in the local population.
Cardiovascular disease (CVD) has accounted for almost one out of three deaths in Singapore over the past few years, which equates to 17 people dying from either heart disease or stroke per day. It is currently ranked as one of the top three causes of hospitalisation and death.1
Progress over the past three decades has led to the discovery of an underlying genetic basis for many CVDs, resulting in the routine use of genetic testing in clinical practice. Some of these conditions are caused by disruption to a single gene that has a deleterious effect, known as monogenic conditions.
These inherited conditions can be divided into:
Many inherited CVDs exhibit phenotypic overlay and genetic heterogeneity, with pathogenic variants in multiple genes causing the same condition.
Analysis can require sequencing the entire region of many genes to identify a genetic cause. Traditional genetic testing methods were time-consuming and expensive as single genes were tested sequentially.
Next generation sequencing (NGS) technologies have enabled large gene sequencing panels containing hundreds of genes of interest to be tested simultaneously at a much lower cost and with reduction in turnaround time. This has vastly increased the accessibility of genetic testing in clinical practice.
More recently, genome-wide association studies (GWAS) have identified a multitude of common genetic variants that underlie risk for the development of common CVDs such as coronary heart disease and atrial fibrillation. Individually these variants have a subtle effect, however collectively they can cause disease, referred to as polygenic risk.
A recent study found that more than 30% of coronary artery disease cases were attributed to genetic factors.3 The utility of genetic testing for polygenic CVD is progressing although not yet widely available for clinical integration.
The main utility of genetic testing is to establish a definitive, etiologically-based diagnosis.
Familial inheritanceIndications of familial inheritance are documented through the collection of over three generations of family medical history information, noting all affected and unaffected family members, and the age of onset and death of any cardiac-related events. The family history information can then be interpreted to assess the likelihood of a genetic condition being present and its inheritance pattern (Table 1).
Age of onsetAdult onset conditions are more often autosomal dominant, whereas childhood conditions can be autosomal dominant, autosomal recessive, X-linked or mitochondrial.6 Prior to genetic testing, screening advice for family members can be recommended according to the family history information.
Who should be testedPatients who clearly meet diagnostic criteria for disease, have a younger age of onset and a family history of CVD have an increased chance of identifying a genetic cause. Therefore, it is recommended to commence testing with the youngest diagnosis in the family or a definitive phenotype.
If genetic testing is performed on individuals with an undefined or borderline diagnosis, the interpretation of the genetic variants and their implications in clinical practice can be inconclusive.
Testing with no family historyGenetic testing is also recommended for patients who do not present with a family history of CVD or sudden death to account for inaccuracies in the collection, incomplete penetrance or variable expression of disease, or the presence of a de novo pathogenic variant.
• Hypertrophic, dilated (non-ischaemic), peripartum, restrictive cardiomyopathy • Arrhythmogenic (right) ventricular cardiomyopathy • Left ventricular non-compaction cardiomyopathy
• Long QT syndrome • Brugada syndrome • Catecholaminergic polymorphic ventricular tachycardia • Unexplained cardiac arrest or sudden death • Sudden infant death syndrome • Atrial fibrillation (<45 years)
Connective tissue disease
• Marfan, Vascular Ehlers-Danlos or Loeys-Dietz syndrome • Aortic aneurysm or dissection (<50 years)
Other inherited conditions
• Familial hypercholesterolemia • Familial or unexplained pulmonary hypertension • Heart attack or coronary heart disease • Heart defects • Familial amyloidosis
• Implantable cardioverter defibrillator or pacemaker implant (<50 years) • Left ventricular assist device or heart transplant (<60 years) • Coronary artery bypass or stent surgery (females <65 years and males <60 years)
Table 1 Adapted from Moscarello, Tia, Chloe Reuter, and Euan A. Ashley. “Is Genetic Testing for Heart Disease Right for Me?.” JAMA Cardiol. 4.9 (2019): 956-956.
Until recently, the recognition of genetic factors predisposing to inherited CVDs has been derived largely from Western cohort studies, with a paucity of data from non-European populations. As genetic variation can be ethnic-specific, this renders challenges in interpreting genomic data from under-represented populations and has previously led to the misdiagnosis and mismanagement of cardiac disease.7 As such, genomic data from diverse populations is required for accurate genetic diagnoses.
Since 2013, the National Heart Centre Singapore (NHCS) has initiated two prospective interlinked cohort studies called Biobank and SingHeart, led by Professor Stuart Cook and Associate Professor Yeo Khung Keong, which collect and store biological samples, health information and imaging data from Singaporeans with CVD (cases) and healthy volunteers (controls).
These studies are contributing to understanding of:
The genomic analysis involves screening a panel of 174 genes with known associations to 17 inherited cardiac conditions which was developed by NHCS.8 The Biobank study has partnered with the SingHealth Duke-NUS Institute of Precision Medicine (PRISM) to perform the genomic analysis and return clinically actionable findings to consenting participants involved.
Establishing a local control groupThe identification of pathogenic variants is complex due to causative variants being rare and often unique to each family, and rare variants occur in individuals with and without disease.
With the creation of a Singaporean genomic control population database (the Singapore Exome Consortium) which comprises aggregated genomic data from over 3,000 “healthy individuals” to date of South East Asian ancestry,9 this enables the frequency of the variants amongst affected individuals to be compared. This local control genomic database aids in distinguishing rare pathogenic variants from benign variants that may be enriched amongst Singaporeans.
Classifying genomic variants To classify each genomic variant, PRISM uses the American College of Medical Genetics and Genomics (ACMG) guidelines10 to characterise variants into five tiers of classification: pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign and benign.
These classifications draw on evidence to include population prevalence data, the effect of the variant to the protein function, segregation of the variant amongst affected family members and presence of the same variant in other patients with the same phenotype.
The data for each possible causative genetic variant is presented at a monthly multidisciplinary team meeting comprising cardiologists, clinical geneticists, genetic counsellors, scientists and bioinformatics experts from SingHealth, and is critically reviewed until consensus regarding pathogenicity is reached. A research report is then generated which documents each monogenic disease and/or carrier risk variant identified, and contains brief information about the associated genetic condition, inheritance and health risks.
A monthly inherited cardiac clinic is held at NHCS where research participants who have consented to receive genetic findings can meet with the clinical genetics team from PRISM (a clinical geneticist and genetic counsellor) and a cardiologist. They are provided information regarding the outcome of genetic testing, genetic variants detected, associated health risk information, and the inheritance, penetrance and implications for family members.
Pathogenic variant detected If a pathogenic variant associated with their clinical diagnosis is detected, research patients are given the opportunity to have the variant clinically validated at a certified laboratory to avoid false positives detected through sequencing, and this requires re-consent for a clinical test. In addition, a new blood sample is collected for variant analysis to avoid the possibility of any sample mix-up at recruitment.
During the consent process, the psychosocial impact of receiving such results, any possible genetic discrimination such as insurance, intention of sharing this information with family members and their possible responses are explored. Patients are then invited back to the clinic to receive the clinical validation results with further discussion regarding medical screening specific to their age and health history. No pathogenic variant reportedIf no pathogenic variants are reported, this could suggest that there is a variant which was either not detected with current technology, or that the presenting phenotype is caused by a combination of polygenic and environmental factors.
In this scenario, cardiac screening advice for family members is assessed according to family history information. When screening multiple genes, the detection of variants of uncertain significance is frequent. As the familial cause of CVD is uncertain, cascade testing is not available to family members. Information regarding variant interpretation does change over time as more knowledge becomes available and test results may be updated with new classifications.
The detection of a pathogenic variant could have implications for lifestyle recommendations, such as exercise; medical therapies; risk to pregnancy; and surgical interventions such as an implantable cardioverter defibrillator, aortic root surgery or heart transplant6 (see Table 2 for examples experienced at the PRISM clinic). Pregnancy planning, if relevant, is also discussed.
Frequently, patients ask how the pathogenic variant will affect their family members, and in particular, their children.
Unfortunately, genetic testing for inherited CVD cannot predict age of onset or severity of disease. However, not everyone carrying a pathogenic variant expresses symptoms (known as reduced penetrance), and individuals within the same family or carrying the same pathogenic variant can be affected differently (known as variable expressivity). Clinical management for family members is advised with disease progression.
Changing clinical management
Understanding triggers for disease onset
Through the NHCS Biobank study, the aggregation of genomic data from CVD patients and the control group of healthy individuals is facilitating the differentiation between pathogenic and benign variants present in our local population. This analysis is leading to a further understanding of genomic variants and their association with CVD.
The identification of pathogenic variants has enabled the clinical management of CVD patients to be refined and their at-risk family members to be identified through cascade testing. Genetic investigations for CVD are rapidly evolving world-wide and will continue to play a vital role in guiding optimal treatment and risk stratification for patients and their families.
If you have a patient with a suspected inherited CVD you may refer them to the
NHCS Cardiogenetics Clinic by contacting:Tel: +65 6704 2222Fax: +65 6222 9258Email: email@example.com
For Biobank study enquiries or those interested in enrolling as a healthy volunteer, please contact:NHCS Biobank CoordinatorsTel: 9159 7029 (office hours 8.30am – 5.30pm)Email: firstname.lastname@example.org
Publications derived from the NHCS Biobank genomic data:
Singapore Heart Foundation.
https://www.myheart.org.sg/myheart/heart-statistics/singapore-statistics. Accessed 30 June 2021.
Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace. 2011;13(8):1077-1109.
Zeng L, Talukdar HA, Koplev S, et al. Contribution of Gene Regulatory Networks to Heritability of Coronary Artery Disease. J Am Coll Cardiol. 2019;73(23):2946-2957.
Cirino AL, Harris S, Lakdawala NK, et al. Role of Genetic Testing in Inherited Cardiovascular Disease: A Review. JAMA Cardiol. 2017;2(10):1153-1160.
Ingles J, Macciocca I, Morales A, Thomson K. Genetic Testing in Inherited Heart Diseases. Heart Lung Circ. 2020;29(4):505-511.
Otto CM, Savla JJ, Hisama FM. Cardiogenetics: a primer for the clinical cardiologist. Heart. 2020;106(12):938-947.
Manrai AK, Funke BH, Rehm HL, et al. Genetic Misdiagnoses and the Potential for Health Disparities. N Engl J Med. 2016;375(7):655- 665.
Pua CJ, Bhalshankar J, Miao K, et al. Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes. J Cardiovasc Transl Res. 2016;9(1):3-11.
Bylstra Y, Kuan JL, Lim WK, et al. Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders. Genet Med. 2019;21(1):207.
Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15(7):565-574.
Yasmin Bylstra is a Principal Genetic Counsellor at the SingHealth Duke-NUS Institute of Precision Medicine (PRISM). She has a key role in the provision of genetic counselling to individuals with or at risk of developing genetic conditions, genomic variant interpretation and population genomics research. She is board-certified with the Human Genetics Society of Australasia (HGSA).
GPs can call the SingHealth Duke-NUS Genomic Medicine Centre for appointments at the following hotlines:KK Women's and Children's Hospital: 6692 2984National Cancer Centre Singapore: 6436 8288
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