Reik W, Brown K W, Slatter R E, Sartori P, Elliott M, Maher E R
Laboratory of Developmental Genetics and Imprinting, Babraham Institute, Cambridge, UK.
Hum Mol Genet. 1994 Aug;3(8):1297-301. doi: 10.1093/hmg/3.8.1297.
Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome with associated embryonal tumours. Most BWS cases are sporadic but familial cases occur in 15% of patients and in these there is linkage to chromosome 11p15. In addition, a small number of patients have cytogenetic abnormalities involving chromosome 11p15. Approximately 20% of sporadic BWS patients have uniparental paternal disomy (UPD) of chromosome 11p15. This finding together with the observation that penetrance in familial cases depends on parental transmission, suggests that the gene(s) for BWS are imprinted. The recent demonstration of biallelic expression of the otherwise maternally imprinted IGF2 gene in some BWS patients implicates excess IGF2 expression in the disease. Here we have analysed the allele-specific methylation patterns in the IGF2 gene and in the neighbouring and reciprocally imprinted H19 gene in a group of 42 BWS patients, 10 of which were mosaic UPD cases. We found that allelic methylation of both genes was normal in all non-UPD cases, with the paternal allele being methylated, and was increased in UPD cases in proportion with the disomic lineage. These findings suggest that sporadic BWS is not associated with a general alteration of methylation imprinting of the IGF2 and H19 genes. The methylation assay used in this study thus also offers a simple and reliable diagnostic test of UPD for 11p15.5. An unexpected finding was a distortion of the frequency of AvaII alleles at the IGF2 locus exclusively in UPD BWS cases (P < 0.001). This further implicates the IGF2 gene in aspects of the BWS phenotype.
贝克威思-维德曼综合征（BWS）是一种伴有胚胎性肿瘤的先天性过度生长综合征。大多数BWS病例为散发性，但15%的患者有家族性病例，且这些家族性病例与11号染色体p15区域存在连锁关系。此外，少数患者存在涉及11号染色体p15区域的细胞遗传学异常。约20%的散发性BWS患者存在11号染色体p15区域的单亲二倍体（UPD），父源单亲二倍体。这一发现以及家族性病例的外显率取决于亲本传递的观察结果表明，BWS相关基因是印记基因。最近在一些BWS患者中发现原本母源印记的IGF2基因出现双等位基因表达，这表明疾病中存在IGF2表达过量。在此，我们分析了42例BWS患者中IGF2基因以及邻近且相互印记的H19基因的等位基因特异性甲基化模式，其中10例为镶嵌型UPD病例。我们发现，在所有非UPD病例中，两个基因的等位基因甲基化均正常，父源等位基因发生甲基化，而在UPD病例中，甲基化随着二倍体谱系增加。这些发现表明，散发性BWS与IGF2和H19基因甲基化印记的普遍改变无关。本研究中使用的甲基化检测方法因此也为11p15.5的UPD提供了一种简单可靠的诊断测试。一个意外发现是，仅在UPD BWS病例中，IGF2基因座处的AvaII等位基因频率出现偏差（P < 0.001）。这进一步表明IGF2基因与BWS表型的某些方面有关。
