Wessex Regional Genetics Laboratory, Salisbury, SP2 8BJ, UK.
Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK.
Clin Epigenetics. 2022 Nov 7;14(1):143. doi: 10.1186/s13148-022-01358-9.
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.
印迹疾病是由基因的遗传或表观遗传变化引起的，这些基因仅从一个亲本等位基因表达，会影响生长、发育、代谢和肿瘤风险。疾病可能由编码序列变化、拷贝数变化、单亲二倍体或印迹缺陷引起。一些印迹疾病具有临床异质性，一些与一个以上印迹基因座相关，一些患者的改变影响多个基因座。大多数印迹疾病通过逐个分析基因剂量和单个基因座的甲基化来诊断，但一些实验室检测与不同印迹疾病相关的基因座组。我们研究了几个使用单基因座和/或多基因座诊断检测的实验室的经验，以探讨不同的检测策略如何影响诊断结果，以及多基因座检测是否有可能提高诊断效率或揭示意想不到的诊断。
我们从七个国家的 11 个实验室收集了数据，涉及 16364 个人和 8 种印迹疾病。在对生长受限障碍 Silver-Russell 综合征进行 4721 人的测试中，731 人具有与该疾病经典相关的 7 号和 11 号染色体改变，但 115 人有意外诊断，涉及非典型分子改变、7 号或 11 号染色体以外的印迹基因座或多基因座印迹障碍。同样，Beckwith-Wiedemann 综合征和其他印迹疾病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，我们讨论了多基因座检测如何为具有经典和不太熟悉的临床印迹疾病的患者优化诊断。此外，我们汇编的数据反映了诊断实验室的日常生活经验，其诊断率低于临床特征明确的队列，并且说明了需要系统地整理临床和分子数据。
