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Trio-Exome-Based Mendelian Inheritance Error Analysis Helps Identify Uniparental Disomies and Resolve Discordant NIPT
Ting Xu1, Qingwen Zeng2, Xinyi Lu1
1Clinical Genetics Center, Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Prenatal Diagnosis
|August 12, 2026
Summary
Mendelian inheritance error (MIE) analysis of trio exome sequencing effectively identifies uniparental disomy (UPD), including heterodisomy (hUPD), often missed by standard methods. This approach resolves discordant noninvasive prenatal testing (NIPT) and explains fetal growth restriction (FGR).
Area of Science:
- Genetics
- Genomic Medicine
Background:
- Uniparental disomy (UPD), especially heterodisomy (hUPD), is an underrecognized cause of fetal growth restriction (FGR) and discordant noninvasive prenatal testing (NIPT).
- Conventional absence-of-heterozygosity (AOH) analysis often fails to detect hUPDs, leading to missed diagnoses.
Purpose of the Study:
- To validate a systematic Mendelian inheritance error (MIE) analysis pipeline using trio exome sequencing (trio-ES).
- To improve the detection of UPD, particularly hUPDs, and resolve ambiguous prenatal findings.
Main Methods:
- A two-stage study analyzed 1948 parent-offspring trios.
- A quantitative biparental inheritance percentage (BPI%) threshold was established and validated.
- The pipeline was prospectively applied to cases of discordant NIPT and unexplained FGR, with orthogonal methylation or short-tandem repeat (STR) analysis for confirmation.
Main Results:
- The MIE pipeline identified 12 clinically significant UPD events using a BPI% < 0.7 threshold.
- 25% (3/12) of identified UPDs were hUPDs missed by standard AOH analysis.
- The pipeline resolved 57.1% of discordant NIPT cases, identifying trisomy rescue and confined placental mosaicism explaining FGR, and detected 8 UPD events in pediatric cases associated with imprinting disorders.
Conclusions:
- MIE analysis of trio-ES data is effective for capturing hUPDs missed by conventional AOH analysis.
- Integrating this pipeline can resolve discordant NIPT results, explain FGR, and enable comprehensive UPD detection.
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