Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), University of Trieste, European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Trieste, Italy.
Cardiovascular Sciences Research Centre, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
Eur J Prev Cardiol. 2023 Jul 12;30(9):871-883. doi: 10.1093/eurjpc/zwad079.
Genotype positive-phenotype negative (GEN+PHEN-) individuals harbour a pathogenic or likely pathogenic variant without exhibiting a phenotypic manifestation of the disease. In the last few years, the widespread use of genetic testing in probands and relatives has increasingly led to the identification of these individuals, with emerging dilemmas regarding their clinical management. A genetic variant may exhibit a variable expressivity even in the same family and spontaneous conversion to overt phenotype is largely unpredictable. Little is known about the possible influence of environmental factors, such intense or moderate exercise with open questions regarding their possible role in promoting or worsening the phenotypic expression. Current guidelines for sports participation in this setting acknowledge the weak burden of evidence and the many uncertainties. The recommendations to engage in intensive exercise and competitive sports are usually contingent on annual clinical surveillance, except for pathogenic variants in specific genes, such as lamin A/C or plakophilin-2. In certain conditions, such as arrhythmogenic cardiomyopathy, guidelines do not differentiate between GEN+PHEN- individuals and patients with overt disease and recommend avoiding participation in high-intensity recreational exercise and competitive sports. It should be emphasized that international guidelines, traditionally restrictive in terms of sports participation and focused on disqualification, embraced recently a more liberal attitude promoting a shared decision-making approach in the absence of clinical markers of increased risk. In this review, we will discuss the current state of knowledge on GEN+PHEN- individuals and the dilemmas surrounding the impact of exercise and prognosis, focusing on cardiomyopathies and channelopathies, which are the predominant causes of sudden cardiac death in the young and in young athletes.
基因型阳性表型阴性（GEN+PHEN-）个体携带有致病性或可能致病性的变异，但没有表现出疾病的表型表现。在过去的几年中，遗传测试在先证者和亲属中的广泛应用越来越多地导致了这些个体的发现，同时也出现了关于其临床管理的难题。即使在同一个家庭中，遗传变异也可能表现出不同的表达性，并且显性表型的自发转化在很大程度上是不可预测的。对于环境因素的可能影响，例如剧烈或中度运动，人们知之甚少，而且对于它们在促进或加重表型表达方面的可能作用仍存在许多疑问。目前，在这种情况下，关于运动参与的指南承认证据薄弱且存在许多不确定性。除了特定基因（如 lamin A/C 或 plakophilin-2）中的致病性变异外，通常建议进行高强度运动和竞技体育，但需要每年进行临床监测。在某些情况下，例如致心律失常性心肌病，指南并未区分 GEN+PHEN-个体和显性疾病患者，建议避免参与高强度娱乐性运动和竞技体育。应该强调的是，国际指南传统上在运动参与方面较为严格，侧重于取消资格，但最近采取了更为宽松的态度，在缺乏增加风险的临床标志物的情况下，促进共同决策方法。在这篇综述中，我们将讨论关于 GEN+PHEN-个体的当前知识状态以及运动和预后的影响所带来的难题，重点讨论心肌病和通道病，这是年轻人和年轻运动员发生心源性猝死的主要原因。
