Considerations for a multiaxis nomenclature system for medical genetics
Considerations for a multiaxis nomenclature system for medical genetics
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DOI：
10.1097/00125817-200107000-00004
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发表时间：
2001-07-01
影响因子：
8.8
通讯作者：
Biesecker, LG
中科院分区：
文献类型：
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作者：
Robin, NH;Biesecker, LG
目前的诊断是基于表型与病因（分子和环境）因素的错误二分法。一些诊断标签仅依赖于表型因素，而另一些则依赖于分子或环境因素。我们提倡考虑一个系统，它可以包括表型和病因因素，并以一种对临床医生和研究人员都统一和有用的方式整合这些因素。直到最近，在没有明确的生化或基因检测的情况下，通过观察到的一系列体征和症状（包括严重和轻微的异常）以及在受影响患者中一致看到的间接实验室检测来诊断综合征或疾病。通常，除了训练有素的临床医生之外，所有人都很难发现可区分的综合征，他们可以辨别相关因素（临床、分子和环境）并做出诊断（所谓的模式识别）。通常不可能知道这些诊断名称是否准确地反映了给定疾病的潜在生物学，或者它们是否仅仅识别了代表多效性的变异。分子技术的进步已经确定了许多遗传综合征和遗传决定疾病的分子基础。对于基础科学家来说，这些发现提供了深入了解基因在正常和异常人类发育和功能中的作用。对于临床医生来说，现在可以进行检测以确认诊断并允许进行产前检查。然而，这些发现也提供了挑战遗传综合征定义的信息。1-3例如，一些临床表现不同的疾病被认为是等位基因，而其他临床表现同质或一致的疾病则被认为是基因座异质性。在某些情况下，分子的进步使得临床或分子命名法本身无法准确描述特定患者的表型。其中一个例子是Apert， Pfeiffer, Crouzon， Jackson-Weiss和sae3 - chotzen颅缝闭锁综合征，这些综合征表现出遗传异质性和多向性。Pfeiffer综合征表型可由基因FGFR1、2或3的突变引起。同样，saethree - chotzen表型也可以由TWIST或FGFR3突变引起。Apert, Crouzon, Pfeiffer， Jackson-Weiss综合征在临床上是不同的（尽管有一些表型重叠），但都是由FGFR2突变引起的。3-5关于这个问题还有很多例子。巨结肠病、结节性硬化症和Bardet-Biedl综合征都是表现出基因座异质性的显性疾病。等位基因多型性多样性的一个例子是GLI3，其中各种等位基因突变导致Grieg头多指综合征、Pallister-Hall综合征和轴后多指a型。这些例子表明，单独考虑表型或病因描述符是不充分的，或者代表了对受影响患者产生诊断标签的相互矛盾的方法。为了解决这个问题，我们建议使用表型和病因因素来产生统一的诊断标签系统。我们首先概述了这种方法的基本假设，然后描述了一个建议的系统。
Current diagnoses are based on a false dichotomy of phenotypic versus etiologic (molecular and environmental) factors. Some diagnostic labels rely solely on phenotypic factors and others rely on molecular or environmental factors. We are advocating consideration of a system that can encompass both phenotypic and etiologic factors and integrate these in a manner that is uniform and useful, both for the clinician and the researcher. Until recently, in the absence of a defining biochemical or genetic test, a syndrome or disorder was diagnosed by the observed constellation of signs and symptoms (including major and minor anomalies), and indirect laboratory tests that were consistently seen together in affected patients. Often the findings that distinguished syndromes were very subtle to all but the trained clinician, who could discern the relevant factors (clinical, molecular, and environmental) and reach a diagnosis (so called pattern recognition). It was often impossible to know if these diagnostic designations accurately reflected the underlying biology of a given disorder or if they merely identified variations that represent pleiotropy. Advances in molecular technology have identified the molecular bases of many genetic syndromes and genetically determined diseases. For basic scientists, these discoveries have provided insight into the role of genes in both normal and abnormal human development and function. For clinicians, testing is now available to confirm a diagnosis and to permit prenatal testing. However, these discoveries have also provided information that has challenged the definition of a genetic syndrome. 1–3 For example, some disorders that appeared clinically distinct were found to be allelic and other disorders that appeared clinically homogenous or consistent demonstrated locus heterogeneity. In some instances, molecular advances have rendered the clinical or molecular nomenclature alone unable to accurately describe a phenotype in a particular patient. One example of this is the craniosynostosis syndromes Apert, Pfeiffer, Crouzon, Jackson-Weiss, and Saethre-Chotzen, which demonstrate both genetic heterogeneity and pleiotropy. The Pfeiffer syndrome phenotype can be caused by mutations in the genes FGFR1, 2, or 3. Similarly, the Saethre-Chotzen phenotype can be caused by mutations in TWIST or FGFR3. Apert, Crouzon, Pfeiffer, Jackson-Weiss syndromes are each clinically distinct entities (albeit with some phenotypic overlap), yet all are caused by FGFR2 mutations. 3–5 There is no shortage of additional examples of this problem. Hirschsprung disease, 6 tuberous sclerosis, 7 and Bardet-Biedl syndrome8 are all phenotypically defined conditions that demonstrate genetic locus heterogeneity. An example of allelic pleiomorphic diversity is GLI3, in which various allelic mutations cause Grieg cephalopolysyndactyly syndrome, Pallister-Hall syndrome, and postaxial polydactyly type A. 9 These examples demonstrate that consideration of either phenotypic or etiologic descriptors alone is either inadequate or represents conflicting approaches to the generation of diagnostic labels for affected patients. To address this issue, we propose that both phenotypic and etiologic factors should be used to generate a unified diagnostic labeling system. We begin by outlining the underlying assumptions of this approach and then delineate a proposed system.