中国育龄妇女不明原因妊娠失败与FMR1基因CGG重复序列相关性研究

There is a a trinucleotide repeat expansion in the 5’untranslated region of the Fragile X Mental Retardation 1(FMR1) gene.The length of the CGG repeat region is highly polymorphic in the general population, ranging from 6 to 44 CGGs. Intermediate alleles range from 45 to 54 CGG repeats, and are not thought to have clinical implications other than the potential to expand to a premutation （PM）in future generations. The permutation allele, present in carriers, contains ∼55 to 200 repeats and does not typically exhibit methylation，but it has the risk to expand to have a child with FXS. PM carriers may also present with fragile X-associated primary ovarian insufficiency (FXPOI). FMR1 full mutation (FM), seen in males and females with fragile X syndrome, contains 200 CGG repeats. Ovarian reserve is directly related to the fecundity and pregnant outcome of women. Therefore, it is very important to explore the relationship of FMR1 gene CGG repeat between of women with unexplained reproductive failure, which has not been reported in the world at present. This study will help women with PM to change their family planning and be good to their family.

FMR1基因启动子区存在着以CGG为单位的动态三联重复。正常人群该序列正常重复范围N=6～44次；中间重复范围为N=45～54次（IM）；当N=55～200时称为前突变（Premature,PM）；CGG重复次数大于200次（Full mutation, FM），为全突变型，全突变的个体将具有典型遗传性智力低下或自闭症等的脆性X综合征的表现。FMR1基因前突变是导致卵巢储备能力下降的主要突变基因之一。卵巢储备功能直接关系的妇女生育能力和妊娠结局，因此对FMR1基因的重复序列的检测来从基因水平探究反复生育失败妇女的原因具有重要意义。目前国内外尚未见有关报道。该研究对改善携带FMR1基因前突变育龄妇女的生育计划，更好的计划生育，促进家庭和谐具有重要的意义

FMR1基因启动子区存在以CGG为单位动态三联重复。正常人该序列重复N=6～44次；中间重复为N=45～54次（IM）当N=55～200时称为前突变（PM）; CGG >200(FM)为全突变型, FM个体具有典型遗传性智力低下或自闭症等脆性X综合征表现。PM是卵巢储备能力下降的主要突变基因之一。卵巢储备功能直接关系妇女生育能力和妊娠结局, 通过对FMR1基因重复序列检测，从基因水平探究反复生育失败妇女的原因，结果如下。.1. 反复流产及卵巢储备能力下降的育龄妇女FMR1基因 CGG 重复次数分布相关性研究:发现39种不同CGG重复数。最常见CGG重复次数是30和29，占总等位基因62.5%。发现16例PM和15例IM，无FM。PM在总人群发病率为1:146，其中反复生育失败组发病率1:369、卵巢早衰组发病率1:35、家族中有自闭症、不明原因智力低下儿出生史组发生率1:6；重复数>100的2例均分布在家族中有自闭症组。.2. 反复流产者FMR1及卵巢功能相关性比较 对260例反复流产者组，与无异常生育史志愿者组140例。发现两组分别有1例IM，余FMR1基因均正常，两组年龄，卵巢功能及FMR1CGG重复数均无统计学差异，P>0.05。.3. 胚胎染色体异常与 FMR1 CGG 重复次数相关性研究43例行早孕人工流产术（对照组）或51例因胚胎停育行手术（研究组）患者，行绒毛染色体检测。研究组染色体异常率显著高于对照组，P<0.01。CGG重复数为IM 2例，两组各1例，染色体正常。绒毛染色体正常组和异常组的CGG重复序列无统计学差异。.4.对FMR1 CGG两条等位基因甲基化初步探索，发现CGG>54 , 另一对等位基因甲基化增加，当CGG≥100高度甲基化>100%。.科学意义：本研究揭示了反复生育异常妇女FMR1基因CGG重复序列分布特点。发现该组人群中行FMR1 PM携带者筛查的价值。家中有自闭症患儿出生妇女应行FMR1筛查。该研究对提高我国人口质量，减少出生缺陷具有重要临床价值。起草了“中国育龄妇女实施FMR1基因筛查共识草案”。成立了 “脆性X综合征联盟”科普公众号。