Our Lady's Children's Hospital Crumlin, Dublin 12, Dublin, Ireland.
School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
Eur J Hum Genet. 2019 Aug;27(8):1178-1185. doi: 10.1038/s41431-019-0391-8. Epub 2019 Apr 12.
Multi-gene testing is useful in genetically heterogeneous conditions, including inherited cardiac pathologies. Increasing the number of genes analysed increases diagnostic yield of variants of certain, likely, or uncertain pathogenicity. Concerns exist regarding management of variants of uncertain/likely pathogenicity in conditions of oligogenic inheritance or variable expressivity. We surveyed a sample of colleagues across different specialties and departments internationally to compare management of patients with class 3 or class 4 variants in genes associated with non-syndromic cardiomyopathy or arrhythmia. An electronic survey regarding clinical management of variants ( www.surveymonkey.com/r/cardiacvariants ) was designed and distributed to colleagues internationally via professional bodies and direct email. 150 respondents (88 centres, 27 countries) completed the survey, most of whom were Clinical Geneticists or Genetic Counsellors. Most respondents offer pre-symptomatic testing to asymptomatic relatives of an individual with class 4 or class 5 variants. A minority of respondents offer pre-symptomatic testing for class 3 variants. Considering class 4 variants, 22 (15%) are fully reassuring that the patient with a negative predictive test would not develop the familial phenotype, while 123 (82%) counselled patients about the possibility of variant reclassification. Variability existed between and within centres and specialties. Multiple "free text" comments were provided. Recurring themes including need for multidisciplinary input, technical concerns, and concern regarding duty to review variants of uncertain significance. This study demonstrates that variability in management of likely pathogenic/uncertain variants exists. Close multi-disciplinary input is essential. The development of disorder or gene-specific evidence-based guidelines might ameliorate uncertainty in management.
多基因检测在遗传异质性条件下很有用，包括遗传性心脏病理学。分析的基因数量增加会增加某些、可能或不确定致病性变异的诊断产量。在寡基因遗传或表现度可变的情况下，对不确定/可能致病性变异的管理存在担忧。我们调查了国际上不同专业和部门的一组同事，比较了管理与非综合征性心肌病或心律失常相关基因的 3 类或 4 类变异患者的方法。我们设计了一个关于变异临床管理的电子调查（www.surveymonkey.com/r/cardiacvariants），并通过专业机构和直接电子邮件向国际同事分发。150 名受访者（88 个中心，27 个国家）完成了调查，其中大多数是临床遗传学家或遗传咨询师。大多数受访者为 4 类或 5 类变异个体的无症状亲属提供无症状前检测。少数受访者为 3 类变异提供无症状前检测。考虑到 4 类变异，22 名（15%）完全确信阴性预测检测的患者不会出现家族表型，而 123 名（82%）向患者咨询了变异重新分类的可能性。中心和专业之间存在差异。提供了多个“自由文本”评论。反复出现的主题包括需要多学科的投入、技术问题以及对审查不确定意义的变异的关注。这项研究表明，对可能致病性/不确定变异的管理存在差异。密切的多学科投入至关重要。制定疾病或基因特异性循证指南可能会减轻管理中的不确定性。
