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Abstract：
BACKGROUND: Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need.
METHODS: A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations.
RESULTS: In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID.
CONCLUSIONS: MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3-5 years to evaluate the research advancements and update this guidance as needed.
METHODS: A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations.
RESULTS: In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID.
CONCLUSIONS: MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3-5 years to evaluate the research advancements and update this guidance as needed.
摘要：
背景：印记障碍是由印记基因表达改变引起的罕见疾病，表现出通过差异DNA甲基化调节的亲本起源特异性表达模式。印迹障碍患者的一个亚组在多个印迹基因座处具有DNA甲基化变化,一种被称为多基因座印记干扰(MLID)的条件。MLID在大多数但不是所有的印记障碍中被识别,并且在具有非典型临床特征的个体中也被发现;MLID的存在经常改变受影响的人的管理或预后。一些MLID病例是由反式作用遗传变异引起的，通常不是在病人身上，而是在他们的母亲身上，具有咨询意义。目前对MLID的定义没有共识，临床适应症提示测试，表观遗传和遗传诊断的分子程序和方法，实验室报告的建议，咨询的考虑，以及对预后和管理的影响。因此，这项研究的目的是涵盖这一尚未满足的需求。
方法：进行了全面的文献检索，鉴定了100多篇文章，这些文章构成了两个工作组的讨论基础，重点是临床诊断（n=12名成员）和分子检测（n=19名成员）。经过八个月的准备和定期的在线讨论，来自11个国家的专家汇编了初步文件，并确定了在面对面会议上需要解决的问题，专家们和四名患者倡导组织的代表出席了会议。
结果：根据现有证据和专家共识，我们制定了16项建议和8项建议,作为MLID临床和分子诊断的中期指导.
结论：MLID是一种分子名称，对于MLID和非典型表型的患者，我们提出了替代术语多位点印记综合征。由于MLID的内在可变性，该指南强调了让各个领域的专家参与以确保自信的诊断方法的重要性，咨询,和关心。作者倡导全球，在基础研究和转化研究方面的合作努力，以解决目前缺乏答案的许多关键问题，并建议在未来3-5年内重新召开会议，以评估研究进展，并根据需要更新本指南。
方法：进行了全面的文献检索，鉴定了100多篇文章，这些文章构成了两个工作组的讨论基础，重点是临床诊断（n=12名成员）和分子检测（n=19名成员）。经过八个月的准备和定期的在线讨论，来自11个国家的专家汇编了初步文件，并确定了在面对面会议上需要解决的问题，专家们和四名患者倡导组织的代表出席了会议。
结果：根据现有证据和专家共识，我们制定了16项建议和8项建议,作为MLID临床和分子诊断的中期指导.
结论：MLID是一种分子名称，对于MLID和非典型表型的患者，我们提出了替代术语多位点印记综合征。由于MLID的内在可变性，该指南强调了让各个领域的专家参与以确保自信的诊断方法的重要性，咨询,和关心。作者倡导全球，在基础研究和转化研究方面的合作努力，以解决目前缺乏答案的许多关键问题，并建议在未来3-5年内重新召开会议，以评估研究进展，并根据需要更新本指南。
