Fernández Esperanza, Gennaro Elena, Pirozzi Filomena, Baldo Chiara, Forzano Francesca, Turolla Licia, Faravelli Francesca, Gastaldo Denise, Coviello Domenico, Grasso Marina, Bagni Claudia
Center for Human Genetics, KU Leuven, Leuven, Belgium.
VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
Front Genet. 2018 Nov 2;9:442. doi: 10.3389/fgene.2018.00442. eCollection 2018.
Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5'UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with one FXS child and another sibling presenting mild intellectual disability and behavioral features evocative of FXS. Genetic characterization of the undiagnosed sibling revealed mosaicism in both the CGG expansion size and the methylation levels in the different tissues analyzed. This report shows that in the same family, two siblings carrying different CGG repeats, one in the full-mutation range and the other in the premutation range, present methylation mosaicism and consequent decreased FMRP production leading to FXS and FXS-like features, respectively. Decreased FMRP levels, more than the number of repeats seem to correlate with the severity of FXS clinical phenotypes.
脆性X综合征（FXS）主要由发生在该基因（Xq27.3）上的两个不同事件引起：基因5'UTR中CGG三联体重复超过200次，以及CGG重复序列上游CpG岛中的胞嘧啶甲基化。在此，我们描述了两个不相关的家庭，每个家庭中有一个患有FXS的儿童，另一个兄弟姐妹表现出轻度智力障碍和类似FXS的行为特征。对未确诊的兄弟姐妹进行基因特征分析发现，在分析的不同组织中，CGG扩增大小和甲基化水平均存在嵌合现象。本报告表明，在同一家庭中，两个携带不同CGG重复序列的兄弟姐妹，一个处于全突变范围，另一个处于前突变范围，均出现甲基化嵌合现象，进而分别导致FMRP产生减少，引发脆性X综合征和类似脆性X综合征的特征。FMRP水平降低似乎比重复次数更能与脆性X综合征临床表型的严重程度相关。
