Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Front Cardiovasc Med. 2016 Jul 25;3:22. doi: 10.3389/fcvm.2016.00022. eCollection 2016.
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.
人类心血管畸形（CVMs）常与遗传因素有关。通过应用新一代测序等新技术，与 CVM 相关的 DNA 序列变异正在快速被鉴定出来。虽然临床医生现在能够为任何患有 CVM 的患者提供 NGS 基因panel 或全外显子组测序的检测，但遗传变异的解释仍然存在问题。表型表达的可变性、降低的外显率、不一致的表型方法以及缺乏对变异的高通量功能测试，都导致了这些挑战。本文详细阐述了影响在 CVM 中广泛实施临床分子遗传学检测的决策的关键问题。检测的主要益处包括：建立遗传诊断、促进对可能有亚临床疾病的家庭成员进行具有成本效益的筛查、预测后代的复发风险、使心血管和非心血管疾病表型能够早期诊断和提前管理、预测长期结果以及促进旨在改善或预防疾病的新型疗法的开发。局限性包括经济成本、心理社会成本以及结果解释的不明确性。多态性家族和有综合征特征的患者是有可能明确确定病因的两类群体。然而，这些只占 CVM 总人群的少数，并且越来越认识到，以前与综合征相关的基因型也存在于缺乏非心血管发现的患者中。在任何情况下，都需要心脏病专家和临床遗传学家之间持续的对话，以准确解释基因检测并改善这些患者的健康状况。这可以通过在致力于为患者进行检测的中心创建和支持心血管遗传学服务来最有效地实现。
