Abstract
Human cardiovascular malformations (CVMs) frequently have a genetic contribution. Through the application of novel technologies, such as next-generation sequencing, DNA sequence variants associated with CVMs are being identified at a rapid pace. While clinicians are now able to offer testing with NGS gene panels or whole exome sequencing to any patient with a CVM, the interpretation of genetic variation remains problematic. Variable phenotypic expression, reduced penetrance, inconsistent phenotyping methods, and the lack of high-throughput functional testing of variants contribute to these challenges. This article elaborates critical issues that impact the decision to broadly implement clinical molecular genetic testing in CVMs. Major benefits of testing include establishing a genetic diagnosis, facilitating cost-effective screening of family members who may have subclinical disease, predicting recurrence risk in offsprings, enabling early diagnosis and anticipatory management of CV and non-CV disease phenotypes, predicting long-term outcomes, and facilitating the development of novel therapies aimed at disease improvement or prevention. Limitations include financial cost, psychosocial cost, and ambiguity of interpretation of results. Multiplex families and patients with syndromic features are two groups where disease causation could potentially be firmly established. However, these account for the minority of the overall CVM population, and there is increasing recognition that genotypes previously associated with syndromes also exist in patients who lack non-CV findings. In all circumstances, ongoing dialog between cardiologists and clinical geneticists will be needed to accurately interpret genetic testing and improve these patients’ health. This may be most effectively implemented by the creation and support of CV genetics services at centers committed to pursuing testing for patients.
Highlights
Cardiovascular malformations (CVMs) are the most common birth defects with an incidence estimated at approximately 8/1000 live births [1]
Molecular genetic testing with next-generation sequencing (NGS) panels is useful for the evaluation of CVM patients in whom a specific genetic syndrome is suspected
NGS panels or whole exome sequencing (WES) may be diagnostic in multiplex families with CVMs
Summary
Cardiovascular malformations (CVMs) are the most common birth defects with an incidence estimated at approximately 8/1000 live births [1]. The common nature of these birth defects, combined with their heterogeneous etiologies, makes genetic evaluation both important and complex. Despite an increasing awareness of the genetic basis of CVMs and the clinical importance of making an accurate diagnosis, there remain many questions about the best approach to clinical application of molecular or cytogenetic testing in individuals with a CVM. We reviewed the utility and limitations of chromosomal microarray analysis (CMA) and the emerging clinical roles for whole exome sequencing (WES) and other NGS technologies for CVMs. Here, we focus on the opportunities and challenges of clinical NGS testing and highlight the importance of phenotyping to improve clinical genetic testing interpretation and to drive etiologycentered research. The integration of genetic findings with deep phenotyping will improve our understanding of disease etiology and advance medical care
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