Liu Shu, Zhang Kaihui, Song Fengling, Yang Yali, Lv Yuqiang, Gao Min, Liu Yi, Gai Zhongtao
Children Inherited Metabolism and Endocrine Department, Guangdong Women and Children Hospital, Guangzhou, China.
Cytogenet Genome Res. 2017;152(1):1-8. doi: 10.1159/000477520. Epub 2017 Jun 24.
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurogenetic disorders caused by loss of function of the imprinted genes at 15q11q13. A 5-7 Mb paternal/maternal deletion of chromosomal region 15q11.2q13 is the major genetic cause of PWS/AS, but in a small group of patients, the PWS/AS phenotype can result from maternal/paternal uniparental disomy (UPD) of chromosome 15. Various mechanisms leading to UPD include gametic complementation, trisomy rescue, and compensatory UPD, which can be inferred from the pattern of uniparental heterodisomy (heteroUPD) or uniparental isodisomy (isoUPD). However, heteroUPD and isoUPD, especially mixed heteroUPD and isoUPD, are very rare in patients with PWS/AS. Here, we report 2 children with PWS/AS caused by mixed segmental heteroUPD 15 and isoUPD 15 which failed to be identified by chromosome microarray (CMA) but could be detected by other molecular genetic methods. The present report unravels the mechanism of mixed iso/heteroUPD 15 in PWS/AS and phenotype-genotype correlations. Moreover, our study suggests that CMA is prone to misdiagnosis for imprinting disorders such as PWS/AS, though it is considered a highly useful tool for copy number variations. As a result, other molecular detection methods, such as methylation analysis and STR marker analysis for UPD, should be supplementary used in this situation.
普拉德-威利综合征（PWS）和安吉尔曼综合征（AS）是由15q11q13印记基因功能丧失引起的神经遗传性疾病。染色体区域15q11.2q13的5-7 Mb父系/母系缺失是PWS/AS的主要遗传原因，但在一小部分患者中，PWS/AS表型可由15号染色体的母系/父系单亲二体性（UPD）导致。导致UPD的各种机制包括配子互补、三体挽救和补偿性UPD，这可以从单亲异二体性（heteroUPD）或单亲同二体性（isoUPD）模式中推断出来。然而，heteroUPD和isoUPD，尤其是混合的heteroUPD和isoUPD，在PWS/AS患者中非常罕见。在此，我们报告2例由15号染色体混合节段性heteroUPD和15号染色体isoUPD引起的PWS/AS患儿，这些患儿通过染色体微阵列（CMA）未能识别，但可通过其他分子遗传学方法检测到。本报告揭示了PWS/AS中15号染色体混合iso/heteroUPD的机制以及表型-基因型相关性。此外，我们的研究表明，尽管CMA被认为是检测拷贝数变异的非常有用的工具，但它容易对PWS/AS等印记障碍产生误诊。因此，在这种情况下，应补充使用其他分子检测方法，如甲基化分析和用于UPD的STR标记分析。
