Centre for Research into Circulating Fetal Nucleic Acids, Li Ka Shing Institute of Health Sciences, Hong Kong, China.
Blood. 2011 Mar 31;117(13):3684-91. doi: 10.1182/blood-2010-10-310789. Epub 2011 Jan 24.
Hemophilia is a bleeding disorder with X-linked inheritance. Current prenatal diagnostic methods for hemophilia are invasive and pose a risk to the fetus. Cell-free fetal DNA analysis in maternal plasma provides a noninvasive mean of assessing fetal sex in such pregnancies. However, the disease status of male fetuses remains unknown if mutation-specific confirmatory analysis is not performed. Here we have developed a noninvasive test to diagnose whether the fetus has inherited a causative mutation for hemophilia from its mother. The strategy is based on a relative mutation dosage approach, which we have previously established for determining the mutational status of fetuses for autosomal disease mutations. In this study, the relative mutation dosage method is used to deduce whether a fetus has inherited a hemophilia mutation on chromosome X by detecting whether the concentration of the mutant or wild-type allele is overrepresented in the plasma of heterozygous women carrying male fetuses. We correctly detected fetal genotypes for hemophilia mutations in all of the 12 studied maternal plasma samples obtained from at-risk pregnancies from as early as the 11th week of gestation. This development would make the decision to undertake prenatal testing less traumatic and safer for at-risk families.
血友病是一种伴 X 连锁遗传的出血性疾病。目前用于血友病的产前诊断方法具有侵入性，会对胎儿造成风险。母体外周血游离胎儿 DNA 分析为这些妊娠提供了一种非侵入性的胎儿性别评估方法。然而，如果不进行突变特异性的确认分析，就无法确定男性胎儿的疾病状态。在这里，我们开发了一种非侵入性的测试方法，用于诊断胎儿是否从其母亲那里遗传了血友病的致病突变。该策略基于相对突变剂量方法，我们之前已经建立了该方法用于确定常染色体疾病突变的胎儿突变状态。在这项研究中，通过检测携带男性胎儿的杂合女性血浆中突变型或野生型等位基因的浓度是否过高，来推断胎儿是否在 X 染色体上遗传了血友病突变。我们在所有 12 个从妊娠 11 周开始的高危妊娠中获得的母体外周血样本中，正确地检测了血友病突变的胎儿基因型。这一进展将使高危家庭做出产前检测的决定变得不那么痛苦和安全。
