Valovičová Kristína, Diderich Karin E M, Bramer Wichor M, Lamballais Sander, Srebniak Malgorzata Ilona
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Section of Genetics and Molecular Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
Prenat Diagn. 2025 Aug;45(9):1139-1150. doi: 10.1002/pd.6822. Epub 2025 May 24.
Monogenic disorders (MDs), often associated with developmental delay, intellectual disability, hypotonia, or dysmorphic facial features, typically go undetected during pregnancy. These disorders are frequently caused by de novo single nucleotide variants (SNVs), which are not currently covered by routine non-invasive prenatal testing (NIPT). This screening gap limits informed decision-making in pregnancy and can lead to the unexpected birth of neonates with severe conditions. The aim of this study was to look for evidence of whether de novo SNVs can be detected through NIPT and to assess the possibility of screening for autosomal dominant MDs in cell-free DNA in maternal plasma.
A systematic literature review conducted on the 27th of February 2024 identified 12 studies examining NIPT of multiple genes associated with MDs. An additional citation analysis for the four most recent studies that were included in the systematic review was conducted on 10th of April 2025. Four additional studies met our inclusion criteria and were incorporated in the final analysis.
The studies demonstrated that next-generation sequencing of a gene panel or whole exome could detect pathogenic single nucleotide variants in fetuses with high positive predictive values 98.9% (66.7%-100%).
This review confirms that performing NIPT for de novo and paternally inherited pathogenic variants associated with MDs is technically possible. Ethical considerations, including disorder selection, variant disclosure, and the need for large-scale implementation studies must be addressed to assess the potential risks and ensure effective and responsible implementation.
单基因疾病（MDs）通常与发育迟缓、智力残疾、肌张力减退或面部畸形特征相关，在孕期往往未被发现。这些疾病常由新生单核苷酸变异（SNV）引起，而目前常规无创产前检测（NIPT）并未涵盖这些变异。这种筛查缺口限制了孕期的知情决策，并可能导致患有严重疾病的新生儿意外出生。本研究的目的是寻找通过NIPT检测新生SNV的证据，并评估在母体血浆游离DNA中筛查常染色体显性MDs的可能性。
2024年2月27日进行的一项系统文献综述确定了12项研究，这些研究检测了与MDs相关的多个基因的NIPT。2025年4月10日对系统综述中纳入的四项最新研究进行了额外的文献引用分析。另外四项研究符合我们的纳入标准，并纳入最终分析。
研究表明，基因panel或全外显子组的下一代测序能够以98.9%（66.7%-100%）的高阳性预测值检测出胎儿中的致病性单核苷酸变异。
本综述证实，对与MDs相关的新生和父系遗传致病性变异进行NIPT在技术上是可行的。必须解决伦理考量，包括疾病选择、变异披露以及大规模实施研究的必要性，以评估潜在风险并确保有效且负责的实施。
