The Ethics of Fragile X Genetic Screening and Testing Across the Lifespan

描述（由申请人提供）：我的长期职业目标是建立一个伦理框架，指导临床医生和政策制定者对行为和发育障碍的基因筛查和测试。由于我在内科、儿科、发育障碍和医学伦理学方面的培训，我有独特的资格来追求这一目标，并成为这一领域的独立研究者。这份K23申请中概述的职业发展计划将加强我迄今为止所接受的培训和经验，并将提供额外的指导和重点来磨练我的技能。行为和发育障碍的遗传诊断在伦理上是复杂的，因为1)这些是终身障碍，症状发作的年龄可变；2)它们挑战了单一基因型与单一疾病表型相关的传统孟德尔范式；3)诊断或其可能性通常会给个人和家庭带来重大的社会耻辱。脆性X综合征（FXS）是遗传性智力迟钝（MR）的最常见原因，拟议的筛查计划强调了当基因型的意义在整个生命周期中变化时，诊断这种疾病的重大伦理挑战。FMR-1基因是多效性的，导致不止一种与临床无关的疾病。基因的完全突变导致FXS伴儿童发病的MR和严重的行为问题。前突变导致卵巢早衰和脆性X震颤共济失调综合征在成人。关于FMR-1诊断策略的现有数据在很大程度上忽略了多效性的复杂性。因此，对于哪些人应该接受检测，在检测前和检测结果呈阳性后应该向患者披露哪些信息，以及携带者向家庭成员披露诊断结果的义务的性质，目前尚无共识。为了提供支持和反对拟议的筛查项目和诊断测试指南的论据，我将对FMR-1携带者诊断的风险和益处进行全面评估。使用定性和定量方法，我将研究主要利益相关者对脆性X新生儿筛查和FMR-1携带者检测的态度，以及诊断的不同含义如何影响家庭信息披露的决策。拟议的研究结果将用于开发R01应用程序，以检查对这些疾病进行基因诊断的终生风险和益处。

DESCRIPTION (provided by applicant): My long-term career goal is to develop an ethical framework to guide both clinicians and policy-makers regarding the genetic screening and testing of behavioral and developmental disorders. Because of my training in Internal Medicine, Pediatrics, Developmental Disabilities, and Medical Ethics, I am uniquely qualified to pursue this goal and to become an independent investigator in this field. The career development plans outlined in this K23 application will enhance the training and experience I have had to date and will provide additional guidance and focus to hone my skills. The genetic diagnosis of behavioral and developmental disorders is ethically complex because 1) these are life-span disorders with variable age of symptom onset; 2) they challenge the traditional Mendelian paradigm in which a single genotype correlates with a single disease phenotype; and 3) the diagnosis or its possibility often carry significant social stigma for the individual and the family. Proposed screening programs for Fragile X Syndrome (FXS), the most common cause of inherited mental retardation (MR), highlight the significant ethical challenges of diagnosing a condition when the meaning of a genotype varies across the lifespan. The FMR-1 gene is pleiotropic, causing more than one clinically-unrelated condition. Full mutations in the gene lead to FXS with child-onset MR and serious behavioral problems. Premutations cause premature ovarian failure and Fragile X Tremor Ataxia Syndrome in adults. Existing data about FMR-1 diagnostic strategies have largely ignored the complexities of pleiotropy. Therefore, there is no current consensus about who should be tested, what information should be disclosed to patients before testing and after a positive result, and the nature of a carriers' obligation to disclose their diagnosis to family members. In order to inform arguments for and against proposed screening programs and diagnostic testing guidelines, I will perform a comprehensive assessment about the risks and benefits of FMR-1 carrier diagnosis. Using qualitative and quantitative methodologies, I will examine the attitudes of primary stakeholders towards Fragile X newborn screening and FMR-1 carrier detection across the lifespan, and how the diverse meanings of the diagnosis influence decisions about familial disclosure. The results of the proposed research will be used to develop an R01 application examining the lifetime risks and benefits of carrying a genetic diagnosis for these conditions.