一个婴儿恶性石骨症家系的植入前遗传学诊断

摘要

目的 探讨植入前遗传学诊断在婴儿恶性石骨症出生缺陷预防中的应用.方法 对1个已明确TCIRG1基因突变的婴儿恶性石骨症家系,应用植入前遗传学诊断技术进行TCIRG1基因突变位点直接测序,并结合选择性遗传标记的单倍型构建进行连锁分析;通过突变位点的直接测序法,对产前绒毛活检和羊水穿刺样本进行遗传学诊断.结果 第3次妊娠时产前基因诊断的结果显示胎儿存在TCIRG1基因c.242delC (p.Pro81Argfs* 85)和c.1114C＞T (p.Gln372*)复合杂合性突变,为遗传了父母双方的致病性突变位点的患儿,选择终止妊娠.随后通过植入前遗传学诊断方法,先后对13个胚胎单卵裂球进行遗传学分析,确定其中6个胚胎为正常,3个胚胎为携带者,4个胚胎为患者.选择了发育良好且遗传学上正常或携带者的胚胎植入母体子宫,受孕后并经产前诊断证实为正常胎儿,足月分娩后随访婴儿正常.结论 反复生育致死性遗传病的家系,在进行遗传咨询时可优先选择植入前遗传学诊断来避免患儿出生.%Objective To explore the application of preimplantation genetic diagnosis (PGD) for infantile malignant osteopetrosis (IMO).Methods For a family affected with IMO,PGD was provided using combined parental mutation detection and haplotype constructions with microsatellite markers spanning the TCIRG1 gene.Prenatal diagnosis was performed on the chorionic villus and amniocentesis samples by direct sequencing.Results Prenatal diagnosis showed that the fetus by the third pregnancy has carried the parental mutations [c.242delC (p.Pro81Argfs * 85) and c.1114C＞T (p.Gln372 *)],and the pregnancy was terminated.PGD was subsequently performed through mutations detection and haplotype analyses following whole genome amplification (WGA) of each of 13 cells.The results showed that 6 of the 13 embryos were unaffected,3 were carriers and 4 were affected.Well developed unaffected/carrier embryos were selected and transferred into the uterus.A single pregnancy was confirmed.Subsequently pre-and post-natal diagnoses have confirmed development of a healthy child.Conclusion The study demonstrated the advantage of PGD over prenatal diagnosis when natural pregnancies have repeatedly produced IMO children/fetuses.