Abstract：
Imprinting disorders, which affect growth, development, metabolism and neoplasia risk, are caused by genetic or epigenetic changes to genes that are expressed from only one parental allele. Disease may result from changes in coding sequences, copy number changes, uniparental disomy or imprinting defects. Some imprinting disorders are clinically heterogeneous, some are associated with more than one imprinted locus, and some patients have alterations affecting multiple loci. Most imprinting disorders are diagnosed by stepwise analysis of gene dosage and methylation of single loci, but some laboratories assay a panel of loci associated with different imprinting disorders. We looked into the experience of several laboratories using single-locus and/or multi-locus diagnostic testing to explore how different testing strategies affect diagnostic outcomes and whether multi-locus testing has the potential to increase the diagnostic efficiency or reveal unforeseen diagnoses.
We collected data from 11 laboratories in seven countries, involving 16,364 individuals and eight imprinting disorders. Among the 4721 individuals tested for the growth restriction disorder Silver-Russell syndrome, 731 had changes on chromosomes 7 and 11 classically associated with the disorder, but 115 had unexpected diagnoses that involved atypical molecular changes, imprinted loci on chromosomes other than 7 or 11 or multi-locus imprinting disorder. In a similar way, the molecular changes detected in Beckwith-Wiedemann syndrome and other imprinting disorders depended on the testing strategies employed by the different laboratories.
Based on our findings, we discuss how multi-locus testing might optimise diagnosis for patients with classical and less familiar clinical imprinting disorders. Additionally, our compiled data reflect the daily life experiences of diagnostic laboratories, with a lower diagnostic yield than in clinically well-characterised cohorts, and illustrate the need for systematising clinical and molecular data.
We collected data from 11 laboratories in seven countries, involving 16,364 individuals and eight imprinting disorders. Among the 4721 individuals tested for the growth restriction disorder Silver-Russell syndrome, 731 had changes on chromosomes 7 and 11 classically associated with the disorder, but 115 had unexpected diagnoses that involved atypical molecular changes, imprinted loci on chromosomes other than 7 or 11 or multi-locus imprinting disorder. In a similar way, the molecular changes detected in Beckwith-Wiedemann syndrome and other imprinting disorders depended on the testing strategies employed by the different laboratories.
Based on our findings, we discuss how multi-locus testing might optimise diagnosis for patients with classical and less familiar clinical imprinting disorders. Additionally, our compiled data reflect the daily life experiences of diagnostic laboratories, with a lower diagnostic yield than in clinically well-characterised cohorts, and illustrate the need for systematising clinical and molecular data.
摘要：
印记障碍,影响生长，发展,代谢和瘤形成风险，是由仅从一个亲本等位基因表达的基因的遗传或表观遗传变化引起的。疾病可能是由编码序列的变化引起的，拷贝数更改,单亲偏见或印记缺陷。一些印记障碍在临床上是异质的，有些与一个以上的印迹位点相关，一些患者有影响多个基因座的改变。大多数印记障碍是通过逐步分析基因剂量和单个基因座的甲基化来诊断的，但是一些实验室分析了一组与不同印迹疾病相关的基因座。我们研究了几个实验室使用单基因座和/或多位点诊断测试的经验，以探讨不同的测试策略如何影响诊断结果，以及多位点测试是否有可能提高诊断效率或揭示不可预见的诊断。
我们从7个国家的11个实验室收集数据,涉及16364个人和八种印记障碍。在4721名测试生长受限障碍Silver-Russell综合征的个体中，731号染色体的7号和11号染色体发生了与该疾病相关的变化，但是115个有意想不到的诊断，涉及非典型的分子变化，除7或11以外的染色体上的印迹基因座或多位点印迹障碍。以类似的方式，在Beckwith-Wiedemann综合征和其他印记障碍中检测到的分子变化取决于不同实验室采用的检测策略.
根据我们的发现,我们讨论了多位点检测如何优化经典和不太熟悉的临床印记障碍患者的诊断。此外,我们收集的数据反映了诊断实验室的日常生活经历，与临床特征明确的队列相比，诊断率较低，并说明需要系统化的临床和分子数据。
我们从7个国家的11个实验室收集数据,涉及16364个人和八种印记障碍。在4721名测试生长受限障碍Silver-Russell综合征的个体中，731号染色体的7号和11号染色体发生了与该疾病相关的变化，但是115个有意想不到的诊断，涉及非典型的分子变化，除7或11以外的染色体上的印迹基因座或多位点印迹障碍。以类似的方式，在Beckwith-Wiedemann综合征和其他印记障碍中检测到的分子变化取决于不同实验室采用的检测策略.
根据我们的发现,我们讨论了多位点检测如何优化经典和不太熟悉的临床印记障碍患者的诊断。此外,我们收集的数据反映了诊断实验室的日常生活经历，与临床特征明确的队列相比，诊断率较低，并说明需要系统化的临床和分子数据。
