[Application value of non-invasive prenatal diagnosis for recessive monogenic genetic diseases based on relative...

Objective: To explore the value of noninvasive prenatal diagnosis for monogenic disorders (NIPD-M) based on relative haplotype dosage (RHDO) and Bayes factor (BF) for pregnant women with high-risk recessive genetic disease in the first trimester. Methods: A total of 206 pregnant women with high-risk recessive genetic disease and pedigree samples at the First Affiliated Hospital of Zhengzhou University between September 2022 and November 2023 were collected. The cell-free DNA (cfDNA) was extracted from the pregnant woman's plasma and the genomic DNA (gDNA) was extracted from the pedigree blood samples. The designed capture panel covered 10 genes (DMD, SMN1, PAH, MMACHC, MMUT, F8, F9, SLC26A4, GJB2, CYP21A2). Sequencing of target regions was performed through high-throughput sequencing platforms, informative single nucleotide polymorphism (SNP) was screened, and pathogenic haplotypes were constructed. The fetal genotype was determined based on the dose change of the informative SNPs in cfDNA combined with the BF algorithm. The circular binary segmentation (CBS) algorithm was used to exclude the interference of recombination events. All NIPD-M results were validated by invasive prenatal diagnosis or newborn genetic testing. Results: Among the recruited families, the median (Q₁, Q₃) age of the 206 pregnant women was 32 (27, 38) years, and the earliest blood collection was at 7 weeks of pregnancy, with the median (Q₁, Q₃) blood collection time of 8⁺² (8, 9⁺²) weeks and fetal fraction (FF) of 5.21% (3.56%, 7.64%). A total of 190 cases were successfully tested, while 16 failed the test, with a success rate of 92.2% (190/206). The NIPD-M results were consistent with the invasive prenatal diagnosis and newborn genetic testing, with the accuracy rate of 100% (190/190). Conclusion: NIPD-M provides an earlier and safer means of prenatal diagnosis for high-risk pregnant women with recessive genetic diseases, with high accuracy and rapid response.