Most copy number variations (CNVs) in the human genome display incomplete penetrance with unknown underlying mechanisms. One such mechanism may be epigenetic modification, particularly DNA methylation. The IMMP2L gene is located in a critical region for autism susceptibility on chromosome 7q (AUTS1). The level of DNA methylation was assessed by bisulfite sequencing of 87 CpG sites in the IMMP2L gene in 3 families with maternally inherited 7q31.1 microdeletions affecting the IMMP2L gene alone. Bisulfite sequencing revealed comparable levels of DNA methylation in the probands, healthy siblings without microdeletions, and their fathers. In contrast, a reduced DNA methylation index and increased IMMP2L expression were observed in lymphocytes from the healthy mothers compared with the probands. A number of genes were upregulated in the healthy mothers compared to controls and downregulated in probands compared to mothers. These genes were enriched in components of the ribosome and electron transport chain, as well as oxidative phosphorylation and various degenerative conditions. Differential expression in probands and mothers with IMMP2L deletions relative to controls may be due to compensatory processes in healthy mothers with IMMP2L deletions and disturbances of these processes in probands with intellectual disability. The results suggest a possible partial compensation for IMMP2L gene haploinsufficiency in healthy mothers with the 7q31.1 microdeletion by reducing the DNA methylation level. Differential DNA methylation of intragenic CpG sites may affect the phenotypic manifestation of CNVs and explain the incomplete penetrance of chromosomal microdeletions.
Cytogenet Genome Res

中文翻译：

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母亲遗传的 7q31.1 微缺失家族中 IMMP2L 基因的差异 DNA 甲基化与智力障碍和发育迟缓有关

人类基因组中的大多数拷贝数变异 (CNV) 显示不完全外显，潜在机制未知。一种这样的机制可能是表观遗传修饰，特别是 DNA 甲基化。所述IMMP2L基因位于临界区对染色体7Q（AUTS1）孤独症易感性。通过对IMMP2L基因中87 个 CpG 位点的亚硫酸氢盐测序评估 DNA 甲基化水平，这些位点具有母系遗传的 7q31.1 微缺失，仅影响IMMP2L基因。亚硫酸氢盐测序揭示了先证者、没有微缺失的健康兄弟姐妹和他们的父亲的 DNA 甲基化水平相当。相比之下，DNA 甲基化指数降低和IMMP2L增加与先证者相比，在来自健康母亲的淋巴细胞中观察到表达。与对照相比，健康母亲的许多基因上调，而先证者的许多基因与母亲相比下调。这些基因富含核糖体和电子传递链的成分，以及氧化磷酸化和各种退化条件。先证者和IMMP2L缺失母亲相对于对照的差异表达可能是由于IMMP2L缺失健康母亲的代偿过程和智障先证者这些过程的干扰。结果表明可能对IMMP2L进行部分补偿通过降低 DNA 甲基化水平，7q31.1 微缺失健康母亲的基因单倍体不足。基因内 CpG 位点的差异 DNA 甲基化可能会影响 CNV 的表型表现并解释染色体微缺失的不完全外显率。
细胞遗传基因组研究