肥厚型心肌病MYH7基因致病突变的产前遗传诊断研究

The Prenatal Genetic Diagnosis in Hypertrophic Cardiomyopathy Patients with Pathogenic Variant of MYH7 Gene

目的在致病突变明确的家系中通过产前遗传诊断来阻断肥厚型心肌病(hypertrophy cardiomyopathy,HCM)的代际传递,减少HCM患者数量。方法对分别携带MYH7基因Arg663Ser和Arg453His致病突变的2例HCM患者进行家系分析,通过Sanger测序检测致病突变位点,通过毛细管电泳进行短串联重复序列(short tandem repeats,STR)分型及及连锁分析。在17-20周行羊穿术采集羊水,羊水细胞提取基因组DNA,进行遗传检测。结果MYH7基因Arg663Ser和Arg453His突变在各自家系中与HCM家系共分离,为所在家系的致病突变。我们选择了杂合度高的6个位于MYH7基因附近的STR(D14S50、D14S283、D14S990、D14S972、D14S64和D14S264)进行分型检测,确认在第一个家系中D14S50的173bp长度等位基因和D14S990的151bp长度等位基因与Arg663Ser突变连锁。在第二个家系中,D14S50的169bp长度等位基因和D14S283的145bp长度等位基因与Arg453His突变连锁。羊水DNA的Sanger测序和STR分型均显示2例胚胎均未携带MYH7基因致病突变。新生儿脐带血的复检结果与产前诊断结果一致。结论产前遗传诊断能够在孕早期明确诊断胎儿是否携带家族HCM致病突变,为咨询者夫妇提供合理的遗传咨询依据,对阻断HCM在家系中遗传具有重要意义。

Objective To explore the feasibility of blocking transmission of hypertrophy cardiomyopathy(HCM)between generations in family with definite pathogenic variants by prenatal genetic diagnosis.Methods Pedigree analysis was performed in two HCM patients with MYH7 Arg663 Ser variant or Arg453 His variant,respectively.Sanger sequencing was used to detect pathogenic variant,and short tandem repeats(STR)classification was achieved by capillary electrophoresis.Amniotic fluid was obtained at 17 th to 20 th week of gestation,and genomic DNA was isolated from amniotic cells and underwent genetic testing.Results Co-segregations of both Arg663 Ser and Arg453 His in MYH7 with HCM were observed among their families.Six STRs(D14 S50,D14 S283,D14 S990,D14 S972,D14 S64 and D14 S264)within or nearby MYH7 and having high heterozygosity were selected for classification analysis.In pedigree 1 the 173 bp allele of D14 S50 and 151 bp allele of D14 S990 linked with Arg663 Ser variant,and in pedigree 2 the 169 bp allele of D14 S50 and 145 bp allele of D14 S283 linked with Arg453 His variant.Sanger sequencing and STR classification of amniotic DNA revealed both fetuses didn’t carry the MYH7 pathogenic variants,which was further confirmed in the umbilical blood of new births.Conclusion Prenatal genetic diagnosis is able to correctly determine whether fetuses inherit the pathogenic variant of HCM from their parents,and providing an important opportunity for blocking the transmission of HCM.