PDF(Pubmed)
Abstract：
UNASSIGNED: Mutations in the GCK gene cause Maturity Onset Diabetes of the Young (GCK-MODY) by impairing glucose-sensing in pancreatic beta cells. During pregnancy, managing this type of diabetes varies based on fetal genotype. Fetuses carrying a GCK mutation can derive benefit from moderate maternal hyperglycemia, stimulating insulin secretion in fetal islets, whereas this may cause macrosomia in wild-type fetuses. Modulating maternal glycemia can thus be viewed as a form of personalized prenatal therapy, highly beneficial but not justifying the risk of invasive testing. We therefore developed a monogenic non-invasive prenatal diagnostic (NIPD-M) test to reliably detect the transmission of a known maternal GCK mutation to the fetus.
UNASSIGNED: A small amount of fetal circulating cell-free DNA is present in maternal plasma but cannot be distinguished from maternal cell-free DNA. Determining transmission of a maternal mutation to the fetus thus implies sequencing adjacent polymorphisms to determine the balance of maternal haplotypes, the transmitted haplotype being over-represented in maternal plasma.
UNASSIGNED: Here we present a series of such tests in which fetal genotype was successfully determined and show that it can be used to guide therapeutic decisions during pregnancy and improve the outcome for the offspring. We discuss several potential hurdles inherent to the technique, and strategies to overcome these.
UNASSIGNED: Our NIPD-M test allows reliable determination of the presence of a maternal GCK mutation in the fetus, thereby allowing personalized in utero therapy by modulating maternal glycemia, without incurring the risk of miscarriage inherent to invasive testing.
UNASSIGNED: A small amount of fetal circulating cell-free DNA is present in maternal plasma but cannot be distinguished from maternal cell-free DNA. Determining transmission of a maternal mutation to the fetus thus implies sequencing adjacent polymorphisms to determine the balance of maternal haplotypes, the transmitted haplotype being over-represented in maternal plasma.
UNASSIGNED: Here we present a series of such tests in which fetal genotype was successfully determined and show that it can be used to guide therapeutic decisions during pregnancy and improve the outcome for the offspring. We discuss several potential hurdles inherent to the technique, and strategies to overcome these.
UNASSIGNED: Our NIPD-M test allows reliable determination of the presence of a maternal GCK mutation in the fetus, thereby allowing personalized in utero therapy by modulating maternal glycemia, without incurring the risk of miscarriage inherent to invasive testing.
摘要：
■GCK基因中的突变通过损害胰腺β细胞中的葡萄糖感应而引起年轻人的成熟性糖尿病(GCK-MODY)。在怀孕期间,这类糖尿病的治疗因胎儿基因型而异.携带GCK突变的胎儿可以从中度母体高血糖中获益，刺激胎儿胰岛胰岛素分泌，而这可能会在野生型胎儿中引起巨大儿。因此，调节母体血糖可以被视为一种个性化的产前治疗。非常有益，但不能证明侵入性测试的风险。因此，我们开发了单基因非侵入性产前诊断（NIPD-M）测试，以可靠地检测已知的母体GCK突变向胎儿的传播。
■母体血浆中存在少量胎儿循环无细胞DNA，但无法与母体无细胞DNA区分开。因此，确定母体突变向胎儿的传播意味着对相邻的多态性进行测序，以确定母体单倍型的平衡。传播的单倍型在母体血浆中过度表达。
■在这里，我们提出了一系列此类测试，其中成功确定了胎儿基因型，并表明它可用于指导怀孕期间的治疗决策并改善后代的结局。我们讨论了该技术固有的几个潜在障碍，以及克服这些问题的策略。
■我们的NIPD-M测试可以可靠地确定胎儿中是否存在母体GCK突变，从而允许通过调节母体血糖进行个性化的子宫内治疗，不会产生侵入性测试固有的流产风险。
■母体血浆中存在少量胎儿循环无细胞DNA，但无法与母体无细胞DNA区分开。因此，确定母体突变向胎儿的传播意味着对相邻的多态性进行测序，以确定母体单倍型的平衡。传播的单倍型在母体血浆中过度表达。
■在这里，我们提出了一系列此类测试，其中成功确定了胎儿基因型，并表明它可用于指导怀孕期间的治疗决策并改善后代的结局。我们讨论了该技术固有的几个潜在障碍，以及克服这些问题的策略。
■我们的NIPD-M测试可以可靠地确定胎儿中是否存在母体GCK突变，从而允许通过调节母体血糖进行个性化的子宫内治疗，不会产生侵入性测试固有的流产风险。
