Journal
HUMAN GENOMICS
Volume 16, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40246-022-00400-4
Keywords
Cell-free DNA; Fetal genotyping; Prenatal diagnosis; Massively parallel sequencing; Monogenic disorder
Categories
Funding
- National Key R&D Program The recognition and identification of genetic pathogenic genes for structural birth defects [2021YFC2701002]
- National Key R&D Program of China [2018YFC1004900]
- National Natural Science Foundation of China [81971344, 82171677, 82192860, 81901495]
- Shanghai Municipal Commission of Science and Technology Program [21Y21901002]
- Shanghai Municipal Health Commission [GW-10.1-XK07]
- CAMS Innovation Fund for Medical Sciences [2019-I2M-5-064]
- Shanghai Municipal Commission of Health and family planning [202140110, 20215Y0216]
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This study demonstrates a cost-effective, less time consuming, and accurate method for noninvasive prenatal diagnosis (NIPD) of monogenic disorders.
Background High-cost, time-consuming and complex processes of several current approaches limit the use of noninvasive prenatal diagnosis (NIPD) for monogenic disorders in clinical application. Thus, a more cost-effective and easily implementable approach is required. Methods We established a low-cost and convenient test to noninvasively deduce fetal genotypes of the mutation and single nucleotide polymorphisms (SNPs) loci by means of targeted amplification combined with deep sequencing of maternal genomic and plasma DNA. The sequential probability ratio test was performed to detect the allelic imbalance in maternal plasma. This method can be employed to directly examine familial pathogenic mutations in the fetal genome, as well as infer the inheritance of parental haplotypes through a group of selected SNPs linked to the pathogenic mutation. Results The fetal mutations in 17 families with different types of monogenic disorders including hemophilia A, von Willebrand disease type 3, Duchenne muscular dystrophy, hyper-IgM type 1, glutaric acidemia type I, Nagashima-type palmoplantar keratosis, and familial exudative vitreoretinopathy were identified in the study. The mutations included various forms: point mutations, gene inversion, deletions/insertions and duplication. The results of 12 families were verified by sequencing of amniotic fluid samples, the accuracy of the approach in fetal genotyping at the mutation and SNPs loci was 98.85% (172/174 loci), and the no-call rate was 28.98% (71/245 loci). The overall accuracy was 12/12 (100%). Moreover, the approach was successfully applied in plasma samples with a fetal fraction as low as 2.3%. Conclusions We have shown in this study that the approach is a cost-effective, less time consuming and accurate method for NIPD of monogenic disorders.
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