Objective: To investigate the clinical (including reproductive) manifestations and genetic characteristics of familial fragile X syndrome (FXS).
Methods: 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.
Results: 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.
Conclusions: 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.
目的: 探讨脆性X染色体综合征（FXS）家系患者包括生殖在内的若干临床表现及其遗传学特征。方法： 通过问诊、睾丸超声检查、精液分析、生殖激素水平测定、外周血核型检查、Y染色体微缺失检查等手段收集1例FXS家系的临床资料，采用Southern印迹测定该家系多个成员X染色体长臂脆性X智力低下-1（FMR1）基因的CGG三联重复序列的大小，确定其FMR1基因的状态（正常、前突变、全突变)并绘制家系图谱。结果： ①经FMR1基因突变检测，该家系4代共34例成员中有3男1女系FMR1全突变患者，占家系成员的11.76%；有9女系FMR1前突变患者，占家系成员的26.47%。② 包括先证者在内的2例全突变FXS男性患者睾丸体积>30 ml，精子浓度高（>250×10⁶/ml），平均精子活力为50.5%，正常形态精子百分率为17.5%，精子核DNA碎片率指数（DFI）为18.5%；生殖激素仅示睾酮低下；外周血染色体核型未见异常，Y染色体也未见缺失。③Ⅱ代4例前突变女性患者中有1例患有卵巢早衰（POF），3例患有子宫肌瘤。结论： 该家系中部分FXS男性患者表现为巨睾症和多精子症,其余精子参数正常；在世代传递中前突变患者可扩展为全突变，且男性的全突变风险高于女性，对于> 80 的CGG三联重复序列前突变患者，其突变遗传给后代及前突变扩展为全突变的风险会有所增加。建议有生育要求者接受基因检测、临床指导和遗传咨询，必要时行产前诊断与植入前胚胎学诊断。.
Keywords: clinical phenotype; fragile X syndrome; genetic characteristics; genetic risk; macroorchidism; premature ovarian failure.