Faculty of Medicine, University of Southampton, Southampton, UK.
Am J Med Genet A. 2013 Sep;161A(9):2174-82. doi: 10.1002/ajmg.a.36049. Epub 2013 Aug 2.
Imprinting disorders are associated with mutations and epimutations affecting imprinted genes, that is those whose expression is restricted by parent of origin. Their diagnosis is challenging for two reasons: firstly, their clinical features, particularly prenatal and postnatal growth disturbance, are heterogeneous and partially overlapping; secondly, their underlying molecular defects include mutation, epimutation, copy number variation, and chromosomal errors, and can be further complicated by somatic mosaicism and multi-locus methylation defects. It is currently unclear to what extent the observed phenotypic heterogeneity reflects the underlying molecular pathophysiology; in particular, the molecular and clinical diversity of multilocus methylation defects remains uncertain. To address these issues we performed comprehensive methylation analysis of imprinted genes in a research cohort of 285 patients with clinical features of imprinting disorders, with or without a positive molecular diagnosis. 20 of 91 patients (22%) with diagnosed epimutations had methylation defects of additional imprinted loci, and the frequency of developmental delay and congenital anomalies was higher among these patients than those with isolated epimutations, indicating that hypomethylation of multiple imprinted loci is associated with increased diversity of clinical presentation. Among 194 patients with clinical features of an imprinting disorder but no molecular diagnosis, we found 15 (8%) with methylation anomalies, including missed and unexpected molecular diagnoses. These observations broaden the phenotypic and epigenetic definitions of imprinting disorders, and show the importance of comprehensive molecular testing for patient diagnosis and management.
印迹紊乱与影响印迹基因的突变和表观突变有关，即那些其表达受亲本来源限制的基因。它们的诊断具有挑战性，原因有二：首先，其临床特征，特别是产前和产后生长障碍，具有异质性且部分重叠；其次，其潜在的分子缺陷包括突变、表观突变、拷贝数变异和染色体错误，并且可能进一步复杂化体细胞镶嵌和多基因位甲基化缺陷。目前尚不清楚观察到的表型异质性在多大程度上反映了潜在的分子病理生理学；特别是，多基因位甲基化缺陷的分子和临床多样性仍不确定。为了解决这些问题，我们对 285 名具有印迹紊乱临床特征的研究队列中的印迹基因进行了全面的甲基化分析，这些患者有或没有阳性的分子诊断。在 91 名被诊断为表观突变的患者中，有 20 名（22%）有额外印迹基因座的甲基化缺陷，这些患者的发育迟缓率和先天性异常发生率高于仅有孤立表观突变的患者，表明多个印迹基因座的低甲基化与临床表现多样性的增加有关。在 194 名具有印迹紊乱临床特征但无分子诊断的患者中，我们发现有 15 名（8%）有甲基化异常，包括漏诊和意外的分子诊断。这些观察结果拓宽了印迹紊乱的表型和表观遗传学定义，并表明全面的分子检测对于患者的诊断和管理非常重要。
