Caliebe Almuth, Richter Julia, Ammerpohl Ole, Kanber Deniz, Beygo Jasmin, Bens Susanne, Haake Andrea, Jüttner Eva, Korn Bernhard, Mackay Deborah J G, Martin-Subero José I, Nagel Inga, Sebire Neil J, Seidmann Larissa, Vater Inga, von Kaisenberg Constantin Sylvius, Temple I Karen, Horsthemke Bernhard, Buiting Karin, Siebert Reiner
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
J Med Genet. 2014 Jun;51(6):407-12. doi: 10.1136/jmedgenet-2013-102149. Epub 2014 Apr 10.
In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. Familial occurrence of multilocus imprinting disorders is rare.
PURPOSE/OBJECTIVE: We have investigated the clinical and molecular features of a familial DNA-methylation disorder.
Tissues of affected individuals and blood samples of family members were investigated by conventional and molecular karyotyping. Sanger sequencing and RT-PCR of imprinting-associated genes (NLRP2, NLRP7, ZFP57, KHDC3L, DNMT1o), exome sequencing and locus-specific, array-based and genome-wide technologies to determine DNA-methylation were performed.
In three offspring of a healthy couple, we observed prenatal onset of severe growth retardation and dysmorphism associated with altered DNA-methylation at paternally and maternally imprinted loci. Array-based analyses in various tissues of the offspring identified the DNA-methylation of 2.1% of the genes in the genome to be recurrently altered. Despite significant enrichment of imprinted genes (OR 9.49), altered DNA-methylation predominately (90.2%) affected genes not known to be imprinted. Sequencing of genes known to cause comparable conditions and exome sequencing in affected individuals and their ancestors did not unambiguously point to a causative gene.
The family presented herein suggests the existence of a familial disorder of DNA-methylation affecting imprinted but also not imprinted gene loci potentially caused by a maternal effect mutation in a hitherto not identified gene.
在由表观突变引起的一部分印记障碍中，多个印记位点会受到影响。多位点印记障碍的家族性发病情况较为罕见。
我们研究了一种家族性DNA甲基化障碍的临床和分子特征。
通过传统和分子核型分析对患病个体的组织以及家庭成员的血液样本进行研究。对印记相关基因（NLRP2、NLRP7、ZFP57、KHDC3L、DNMT1o）进行桑格测序和逆转录聚合酶链反应，进行外显子测序以及基于位点、阵列和全基因组技术以确定DNA甲基化情况。
在一对健康夫妇的三个后代中，我们观察到严重生长发育迟缓及畸形在产前出现，且与父源和母源印记位点的DNA甲基化改变相关。对后代不同组织进行基于阵列的分析发现，基因组中2.1%的基因的DNA甲基化反复发生改变。尽管印记基因有显著富集（比值比9.49），但DNA甲基化改变主要（90.2%）影响的是未知为印记的基因。对已知会导致类似病症的基因进行测序以及对患病个体及其祖先进行外显子测序，均未明确指出致病基因。
本文所呈现的这个家族提示存在一种家族性DNA甲基化障碍，它会影响印记基因位点以及非印记基因位点，可能是由一个迄今未被识别基因中的母系效应突变所导致。
