Faculty of Health and Life Sciences, University of Exeter Medical School, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
Diabetologia. 2023 Nov;66(11):1997-2006. doi: 10.1007/s00125-023-05982-9. Epub 2023 Aug 31.
AIMS/HYPOTHESIS: In pregnancies where the mother has glucokinase-MODY (GCK-MODY), fetal growth is determined by fetal genotype. When the fetus inherits a maternal pathogenic GCK variant, normal fetal growth is anticipated, and insulin treatment of maternal hyperglycaemia is not recommended. At present, fetal genotype is estimated from measurement of fetal abdominal circumference on ultrasound. Non-invasive prenatal testing of fetal GCK genotype (NIPT-GCK) using cell-free DNA in maternal blood has recently been developed. We aimed to compare the diagnostic accuracy of NIPT-GCK with that of ultrasound, and determine the feasibility of using NIPT-GCK to guide pregnancy management.
We studied an international cohort of pregnant women with hyperglycaemia due to GCK-MODY. We compared the diagnostic accuracy of NIPT-GCK with that of measurement of fetal abdominal circumference at 28 weeks' gestation (n=38) using a directly genotyped offspring sample as the reference standard. In a feasibility study, we assessed the time to result given to clinicians in 43 consecutive pregnancies affected by GCK-MODY between July 2019 and September 2021.
In terms of diagnostic accuracy, NIPT-GCK was more sensitive and specific than ultrasound in predicting fetal genotype (sensitivity 100% and specificity 96% for NIPT-GCK vs sensitivity 53% and specificity 61% for fetal abdominal circumference 75th percentile). In terms of feasibility, a valid NIPT-GCK fetal genotype (≥95% probability) was reported in all 38 pregnancies with an amenable variant and repeated samples when needed. The median time to report was 5 weeks (IQR 3-8 weeks). For the 25 samples received before 20 weeks' gestation, results were reported at a median gestational age of 20 weeks (IQR 18-24), with 23/25 (92%) reported before 28 weeks.
CONCLUSIONS/INTERPRETATION: Non-invasive prenatal testing of fetal genotype in GCK-MODY pregnancies is highly accurate and is capable of providing a result before the last trimester for most patients. This means that non-invasive prenatal testing of fetal genotype is the optimal approach to management of GCK-MODY pregnancies.
目的/假设：在母亲患有葡萄糖激酶- MODY（GCK-MODY）的妊娠中，胎儿的生长取决于胎儿的基因型。当胎儿遗传母体致病性 GCK 变异时，预计胎儿会正常生长，不建议对母体高血糖进行胰岛素治疗。目前，通过超声测量胎儿腹围来估计胎儿基因型。最近已经开发出了使用母体血液中的游离 DNA 进行无创产前检测胎儿 GCK 基因型（NIPT-GCK）的方法。我们旨在比较 NIPT-GCK 与超声的诊断准确性，并确定使用 NIPT-GCK 来指导妊娠管理的可行性。
我们研究了一个国际妊娠妇女队列，这些妇女因 GCK-MODY 而出现高血糖。我们比较了 NIPT-GCK 与 28 周妊娠时测量胎儿腹围（n=38）的诊断准确性，以直接基因分型的后代样本作为参考标准。在一项可行性研究中，我们评估了 2019 年 7 月至 2021 年 9 月期间 43 例受 GCK-MODY 影响的连续妊娠中，将结果提供给临床医生的时间。
就诊断准确性而言，NIPT-GCK 比超声更能准确预测胎儿基因型（NIPT-GCK 的敏感性为 100%，特异性为 96%，而胎儿腹围 75 百分位的敏感性为 53%，特异性为 61%）。就可行性而言，在所有可分析变异的 38 例妊娠中，均报告了有效的 NIPT-GCK 胎儿基因型（≥95%的概率），当需要重复样本时也是如此。报告的中位数时间为 5 周（IQR 3-8 周）。对于在 20 周妊娠前收到的 25 个样本，结果报告的中位妊娠龄为 20 周（IQR 18-24 周），其中 23/25（92%）在 28 周前报告。
结论/解释：在 GCK-MODY 妊娠中进行胎儿基因型的无创产前检测具有很高的准确性，并且能够为大多数患者在妊娠晚期前提供结果。这意味着，对胎儿基因型进行无创产前检测是 GCK-MODY 妊娠管理的最佳方法。
