PDF(Sci-hub)
Abstract：
Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance.
Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found.
We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss.
The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.
Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found.
We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss.
The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.
摘要：
基因组印记是由于种系表观遗传标记对早期胚胎中少量哺乳动物基因的重编程的抗性。遗传,防止印记逃避重编程的表观遗传或环境损害可能导致印记障碍，影响增长，发展,行为和新陈代谢。我们旨在通过全外显子组测序在一个或多个成员受多基因座印迹障碍影响的家庭中确定导致印迹障碍的遗传缺陷。
在先证者有多位点印记障碍的38个家系中进行了全外显子组测序，其中5人先前发现了NLRP5的母体变异。
我们现在报告了15个进一步的家谱，其中后代有印记的干扰，虽然他们的母亲很少，预测母体效应基因中的有害变异，包括NLRP2、NLRP7和PADI6。以及公认的印记障碍的临床特征，一些后代有其他特征，包括发育迟缓，行为问题和不一致的单卵孪生，而一些母亲有生殖问题，包括怀孕失败。
在38个受多基因座印迹障碍影响的家庭中，对20个推定的母体效应变异的鉴定增加了证据，即母体遗传因素会影响卵母细胞的适应性，从而影响后代的发育。在受非典型印记障碍影响的家庭中，应考虑对母体效应遗传变异进行测试。
在先证者有多位点印记障碍的38个家系中进行了全外显子组测序，其中5人先前发现了NLRP5的母体变异。
我们现在报告了15个进一步的家谱，其中后代有印记的干扰，虽然他们的母亲很少，预测母体效应基因中的有害变异，包括NLRP2、NLRP7和PADI6。以及公认的印记障碍的临床特征，一些后代有其他特征，包括发育迟缓，行为问题和不一致的单卵孪生，而一些母亲有生殖问题，包括怀孕失败。
在38个受多基因座印迹障碍影响的家庭中，对20个推定的母体效应变异的鉴定增加了证据，即母体遗传因素会影响卵母细胞的适应性，从而影响后代的发育。在受非典型印记障碍影响的家庭中，应考虑对母体效应遗传变异进行测试。
