孕期遗传性耳聋热点致病基因突变筛查及高风险妊娠的产前诊断

Screening for hotspot mutations associated with genetic hearing impairment in pregnant women and subsequent prenatal diagnosis in high risk pregnancies

目的对孕期女性进行中国人群遗传性耳聋热点基因突变筛查，并对高风险家庭进行妊娠风险评估及产前诊断。方法2012年11月至2017年10月期间对26 117名孕妇采用分子杂交芯片方法进行4个遗传性耳聋相关基因共9个热点突变的筛查（GJB2基因c. 35 del G、c. 176_191 del 16 bp、c. 235 del C、c.299_300 del AT，GJB3基因c. 538 C〉T，SLC26A4基因c. 2168 A〉G、IVS7－2 A〉G，线粒体DNA 12S rRNA基因m. 1494 C〉T、m. 1555 A〉G）；对携带致聋基因突变孕妇的配偶进行基因型分析，并对存在耳聋高风险的胎儿进行产前诊断。结果接受筛查的孕妇中，携带耳聋基因突变者共1 208例（4.63%），其中7例为同一基因纯合突变或复合杂合突变的听力障碍患者，51例为线粒体基因突变携带者，103例为GJB3基因c. 538 C〉T杂合变异携带者，1 026例为GJB2或SLC26A4杂合突变携带者，21例同时携带两个基因杂合突变。394例孕妇的配偶进行了相关基因的序列分析，发现27个家庭孕妇与丈夫均携带同一耳聋致病基因突变。其中18个家庭行产前诊断，5例胎儿被检测为遗传性耳聋患儿，终止妊娠；未行产前诊断的9例中1例产后确诊为复合杂合子。结论对孕妇进行耳聋基因筛查并对高风险妊娠进行产前诊断，可以有效防止遗传性耳聋患儿的出生。

ObjectiveTo screen for hotspot gene mutations associated with genetic deafness in Chinese pregnant women, and to perform risk assessment and prenatal diagnosis in high-risk families.MethodsBetween November 2012 and October 2017, 26 117 pregnant women were screened by molecular hybridization microarray for 9 hot-spot mutations in 4 hereditary deafness related genes （GJB2 c. 35 del G, c. 176_191 del 16 bp, c. 235 del G, c. 299_300 del AT, GJB3 c. 538 C〉T, SLC26A4 c. 2168 A〉G, IVS 7-2 A〉G, mitochondrial DNA 12S rRNA m. 1494 C〉T, m. 1555 A〉G）. Genotype analysis was carried out in husbands of women carrying mutations, and prenatal diagnosis was carried out in the fetuses with high risk of deafness.ResultsAmong all women tested, 1 208（4.63%） were carriers of genetic deafness mutations, 7 with hearing impairment were affected by homozygous or compound heterozygous mutations, 51 were mitochondrial gene mutation carriers, 103 were carriers of GJB3 c. 538 C〉T heterozygous mutation, 1 026 were carriers of GJB2 or SLC26A4 heterozygous mutations, and 21 carried heterozygous mutations in two genes simultaneously. In 394 families, the husbands accepted gene sequence testing, and 27 in which were determined as carriers of mutations in identical genes as their wives. Among which, 18 families received prenatal diagnosis, and 5 fetuses were diagnosed as hereditary deafness. In 9 families who did not receive prenatal diagnosis, 1 neonate was diagnosed as compound heterozygote after delivery.ConclusionIn order to prevent birth defects with congenital hearing problems, it is effective to provide screening for hotspot mutations in pregnant women and to perform prenatal diagnosis on high risk pregnancies.