一个生殖腺嵌合Becker型肌营养不良症家系行产前诊断和胚胎植入前遗传学诊断的分析

Genetic analysis of a gonadal-mosaicism BMD family with prenatal diagnosis and PGT-M

目的明确一个疑似生殖腺嵌合Becker型肌营养不良症(BMD)家系致病特点, 为类似家系妊娠选择提供依据。方法系统回顾2012年6月至2019年9月于湖南家辉遗传专科医院收治的1个BMD家系, 查阅先证者病史与家族史, 应用多重连接探针扩增技术检测先证者、胎儿、父母Duchenne型肌营养不良症(DMD)基因79个外显子缺失/重复变异, 并结合PCR扩增、短核苷酸串连重复多态性连锁分析以及实时荧光定量PCR等技术对检测结果进行验证。经胚胎植入前遗传学检测, 筛选优质胚胎进行移植, 于孕中期采集羊水进行产前诊断验证。结果根据先证者表型分析, 临床初诊为BMD, 检测到DMD基因45~50号外显子缺失。其母亲外周血中未检测到该突变, 再次妊娠时, 产前诊断结果示胎儿与先证者存在相同的缺失突变。胚胎植入前遗传学检测的2枚胚胎均未携带该缺失, 进行单胚移植并成功妊娠, 孕期产前诊断确认后, 足月剖宫产分娩1名健康女婴。结论该BMD家系为连续发生2次BMD同种缺失型突变妊娠家系, 且先证者母亲外周血和2枚胚胎细胞中未检测到DMD基因该缺失, 提示其母亲可能为该缺失突变生殖腺嵌合携带者, 产前诊断和胚胎植入前遗传学检测技术的联合应用为有效避免类似患儿出生提供了参考途径。

Objective To identify the pathogenic characteristics of a suspected gonadal mosaicism Becker muscular dystrophy(BMD)family,and provide provide basis for pregnancy selection of similar families.Methods A BMD family admitted to Hunan Jiahui Genetics Hospital from June 2012 to September 2019 was systematically reviewed.The medical history and family history of the proband were checked,and multiplex ligation-dependent probe amplification was used to detect the deletion/duplication of 79 exons of the Duchenne muscular dystrophy(DMD)gene in the proband,fetuses,and parents.Moreover,potential variants were verified by combining PCR amplification,short tandom repeat polymorphic linkage analysis,and real-time fluorescence quantitative PCR.High-quality embryos are screened for transplantation after preimplantation genetic testing for monogenic(PGT-M).And amniotic fluid was collected in the second trimester for prenatal diagnostic verification.Results According to the phenotype analysis of the proband,the initial clinical diagnosis was BMD,and the exon 45-50 deletion in DMD gene was detected.The mutation was not detected in the mother′s peripheral blood,but when she was pregnant again,the prenatal diagnosis showed that the fetus had the same deletion mutation as the proband.Neither of two vitro embryos tested by PGT-M has the deletion mutation,then single embryo transfer was performed nor was pregnancy successful.After confirmation of prenatal diagnosis during pregnancy,a normal baby girl was born by full-term cesarean section.Conclusions This BMD family was a family with two consecutive BMD homodeletion mutations,and the mutation of the DMD gene was not detected in the peripheral blood of the proband′s mother and two embryonic cells,suggesting that the mother may be a gonad chimeric carrier of this deletion mutation.The combined application of prenatal diagnosis and PGT-M provides a reference approach to effectively avoid the birth of similar children.