The Current Landscape of Genetic Testing in Cardiovascular Malformations: Opportunities and Challenges

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.

Keywords: congenital heart disease; genetics; genomics; mutation; next-generation sequencing; phenomics; phenotyping.

Figure 1

Schematic outlining the clinical implementation of CVM genetic testing. (A) Deep phenotyping data include complete CVM diagnoses, congenital non-CV malformations, dysmorphic exam findings, neurodevelopmental abnormalities, and other pertinent medical history. Specification of relevant negative findings, including radiographic studies (e.g., head/renal ultrasound), neurodevelopmental evaluation, and specific cardiac evaluations, is important for robust datasets. Age that diagnoses were established or ruled out should be included. Phenotype data should be collected in a structured format (e.g., HPO). (B) Family history data are input as a three-generation pedigree, including documentation of relatives with negative cardiac screening. (C) Prior genetic testing results data include dates and testing laboratory. (D) Genetic testing decisions are patient, family, and disease differential specific. Current clinically available testing options include single gene (e.g., sequencing or deletion/duplication testing), multiple gene (e.g., NGS panels), or genome-wide (e.g., chromosomal analysis, CMA, or whole exome sequencing) testing. (E) Laboratory interpretation of genetic testing is based upon ACMG guidelines. High-quality patient data should be provided with the orders for genetic testing. (F) Clinical interpretation of genetic testing combines multidisciplinary CV genetics knowledge/expertise with the laboratory interpretation. (G) Direct clinical use includes providing results and counseling to family, reporting to health-care providers, recommending treatment, making appropriate subspecialty referrals, making appropriate plan for longitudinal monitoring, and instituting cascade genetic testing and/or family-based cardiac imaging as indicated. (H) Local database compiles high-quality phenotype and genotype data for multiple uses, including longitudinal follow up (e.g., completion of cardiac screening in family members or reassessment of variant interpretation), documentation of clinical practices and outcomes, and periodic data harvests for dissemination to public databases and peer-reviewed publication.