Sha Yan-Wei, Ding Lu, Ji Zhi-Yong, Mei Li-Bin, Li Ping, Li Zheng
Department of Reproductive Medicine, Xiamen Maternity and Child Health Hospital, Xiamen, Fujian 361003, China.
Center of Urology, The First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China.
Zhonghua Nan Ke Xue. 2016 Sep;22(9):797-804.
To investigate the clinical (including reproductive) manifestations and genetic characteristics of familial fragile X syndrome (FXS).
We collected the clinical data about a case of familial FXS by inquiry, testicular ultrasonography, semen analysis, determination of sex hormone levels, and examinations of the peripheral blood karyotype and Y chromosome microdeletions. Using Southern blot hybridization, we measured the size of the CGG triple repeat sequence of the fragile X mental retardation-1 (FMR1) gene and determined its mutation type of the pedigree members with a genetic map of the FXS pedigree.
Among the 34 members of 4 generations in the pedigree, 3 males and 1 female (11.76%) carried full mutation and 9 females (26.47%) premutation of the FMR1 gene. Two of the males with full FMR1 mutation, including the proband showed a larger testis volume (>30 ml) and a higher sperm concentration (>250 ×10⁶/ml), with a mean sperm motility of 50.5%, a mean morphologically normal sperm rate of 17.5%, an average sperm nuclear DNA fragmentation index (DFI) of 18.5%, a low level of testosterone, normal karyotype in the peripheral blood, and integrity of the azoospermia factor (AZF) region in the Y chromosome. One of the second-generation females carrying FMR1 premutation was diagnosed with premature ovarian failure and another 3 with uterine myoma.
Some of the FXS males in the pedigree may present macroorchidism and polyzoospermia but with normal semen parameters. In the intergenerational transmission, premutation might extend to full mutation, with even higher risks of transmission and extension of mutation in males, especially in those with >80 CGG triple repeat sequences. Therefore, it is recommended that the couples wishing for childbearing receive genetic testing, clinical guidance, and genetic counseling before pregnancy and, if necessary, prenatal diagnosis and preimplantation genetic diagnosis.
探讨家族性脆性X综合征（FXS）的临床（包括生殖方面）表现及遗传学特征。
通过询问、睾丸超声检查、精液分析、性激素水平测定、外周血核型及Y染色体微缺失检测等方法，收集1例家族性FXS患者的临床资料。采用Southern印迹杂交技术，测量脆性X智力低下1（FMR1）基因CGG三核苷酸重复序列的大小，并利用FXS家系遗传图谱确定家系成员的突变类型。
该家系4代34名成员中，3名男性和1名女性（11.76%）携带FMR1基因全突变，9名女性（26.47%）携带前突变。2名携带FMR1基因全突变的男性，包括先证者，睾丸体积较大（>30 ml），精子浓度较高（>250×10⁶/ml），平均精子活力为50.5%，平均形态正常精子率为17.5%，平均精子核DNA碎片指数（DFI）为18.5%，睾酮水平较低，外周血核型正常，Y染色体无精子因子（AZF）区域完整。1名携带FMR1基因前突变的第二代女性被诊断为卵巢早衰，另外3名患有子宫肌瘤。
该家系部分FXS男性可能表现为睾丸增大和精子增多，但精液参数正常。在代际传递中，前突变可能扩展为全突变，男性尤其是携带>80个CGG三核苷酸重复序列的男性，突变传递和扩展的风险更高。因此，建议有生育意愿的夫妇在孕前接受基因检测、临床指导和遗传咨询，必要时进行产前诊断和植入前基因诊断。
