Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
Mol Genet Genomic Med. 2020 Apr;8(4):e1192. doi: 10.1002/mgg3.1192. Epub 2020 Feb 25.
A pair of dizygotic twins discordantly affected by heavy prenatal alcohol exposure (PAE) was reported previously by Riikonen, suggesting the role of genetic risk or protective factors in the etiology of alcohol-induced developmental disorders. Now, we have re-examined these 25-year-old twins and explored genetic origin of the phenotypic discordancy reminiscent with fetal alcohol syndrome (FAS). Furthermore, we explored alterations in DNA methylation profile of imprinting control region at growth-related insulin-like growth factor 2 (IGF2)/H19 locus in twins' white blood cells (WBC), which have been associated earlier with alcohol-induced genotype-specific changes in placental tissue.
Microarray-based comparative genomic hybridization (aCGH) was used to detect potential submicroscopic chromosomal abnormalities, and developmental as well as phenotypic information about twins were collected. Traditional bisulfite sequencing was used for DNA methylation analysis.
Microarray-based comparative genomic hybridization revealed a microdeletion 18q12.3-q21.1. in affected twin, residing in a known 18q deletion syndrome region. This syndrome has been associated with growth restriction, developmental delay or intellectual deficiency, and abnormal facial features in previous studies, and thus likely explains the phenotypic discordancy between the twins. We did not observe association between WBCs' DNA methylation profile and PAE, but interestingly, a trend of decreased DNA methylation at the imprinting control region was seen in the twin with prenatal growth retardation at birth.
The microdeletion emphasizes the importance of adequate chromosomal testing in examining the etiology of complex alcohol-induced developmental disorders. Furthermore, the genotype-specific decreased DNA methylation at the IGF2/H19 locus cannot be considered as a biological mark for PAE in adult WBCs.
此前 Riikonen 报道了一对受重度产前酒精暴露（PAE）影响的异卵双胞胎，这表明遗传风险或保护因素在酒精引起的发育障碍病因学中起作用。现在，我们重新检查了这对 25 岁的双胞胎，并探讨了与胎儿酒精综合征（FAS）相似的表型不一致的遗传起源。此外，我们还研究了双胞胎白细胞（WBC）中与生长相关的胰岛素样生长因子 2（IGF2）/H19 基因座印迹控制区的 DNA 甲基化谱的变化，这些变化与酒精引起的胎盘组织中特定基因型变化有关。
使用基于微阵列的比较基因组杂交（aCGH）检测潜在的亚微观染色体异常，并收集有关双胞胎的发育和表型信息。传统的亚硫酸氢盐测序用于 DNA 甲基化分析。
基于微阵列的比较基因组杂交显示，受影响的双胞胎存在 18q12.3-q21.1 微缺失，位于已知的 18q 缺失综合征区域。该综合征与生长受限、发育迟缓或智力缺陷以及先前研究中的异常面部特征有关，因此可能解释了双胞胎之间的表型不一致。我们没有观察到 WBCs 的 DNA 甲基化谱与 PAE 之间存在关联，但有趣的是，在出生时存在产前生长迟缓的双胞胎中，印迹控制区的 DNA 甲基化呈下降趋势。
微缺失强调了在检查复杂酒精引起的发育障碍病因时进行充分染色体检测的重要性。此外，IGF2/H19 基因座的特定基因型 DNA 甲基化降低不能被认为是成年 WBC 中 PAE 的生物学标志。
