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Updated: Jul 9, 2026
Pre-Implantation Genetic Testing for Aneuploidy on a Semiconductor Based Next-Generation Sequencing Platform
Published on: August 17, 2022
A novel comprehensive non-invasive prenatal testing system for the simultaneous detection of single-gene disorders,
Yichen Zhang1, Yiming Wu1, Zhenle Pei1
1Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, MOE Engineering Research Center of Gene Technology, State Key Laboratory of Genetic Engineering, Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China.
Objectives:
Invasive prenatal diagnosis is recommended for high-risk pregnancies, but many decline due to potential complications. To date, no non-invasive prenatal testing (NIPT) simultaneously detects monogenic diseases, balanced chromosomal rearrangements (BCRs), and aneuploidies. We developed a comprehensive NIPT to detect monogenic diseases, aneuploidies, and BCRs concurrently.
Methods:
We recruited eight families at risk for both monogenic disorders and BCRs. A custom capture-based single nucleotide polymorphism (SNP) panel targeting ∼60,000 loci was synthesized for target sequencing. Parental haplotypes were determined by genotyping family members. Maternal plasma DNA was sequenced and fetal haplotypes inferred by a Hidden Markov Model (HMM) to predict inheritance at targeted gene regions and rearrangement breakpoints. To validate the method's accuracy, inferred fetal genotypes were compared with amniocentesis; fetal karyotyping and a genome-wide comparison of inferred fetal genotypes were conducted in a single-blinded manner.
Results:
All participants conceived via assisted reproductive technology. Sequencing depth averaged 200× across the 6.33 Mb target regions for cell-free DNA analysis, and the sequencing error rate ranged 0.045-0.123 % (mean 0.067 %) across all eight families. Haplotype construction succeeded for all families, enabling accurate identification of disease-causing genes and fetal karyotypes. Genotype analysis showed high accuracy for paternal and maternal informative SNPs (99.89 and 97.54 %, respectively). Fetal results from NIPT were completely concordant with invasive diagnostics.
Conclusions:
Our haplotype-based NIPT detects a broad spectrum of fetal genetic variations, simultaneously identifying monogenic diseases and chromosomal aberrations, and is clinically applicable as a valuable means of NIPT for the current genetic disease diagnosis.
