Trio-Exome-Based Mendelian Inheritance Error Analysis Helps Identify Uniparental Disomies and Resolve Discordant NIPT Findings.

OBJECTIVE: Uniparental disomy (UPD), particularly heterodisomy (hUPD), is an underdiagnosed etiology in cases of fetal growth restriction (FGR) and discordant noninvasive prenatal testing (NIPT). Because conventional absence-of-heterozygosity (AOH) analysis frequently misses hUPDs, we aimed to validate a systematic Mendelian inheritance error (MIE) analysis pipeline for trio exome sequencing (trio-ES) to resolve ambiguous prenatal findings. METHOD: A two-stage study analyzed 1948 parent-offspring trios (postnatal and prenatal samples). A retrospective cohort (n = 992) established and validated a quantitative biparental inheritance percentage (BPI%) threshold. This workflow was prospectively applied (n = 956) to evaluate clinical utility, focusing on discordant NIPT and unexplained fetal growth restriction (FGR). Orthogonal analysis of methylation or short-tandem repeats (STR) were used to confirm identified UPD. RESULTS: Utilizing a BPI% < 0.7 threshold, the pipeline identified 12 clinically significant UPD events. Crucially, 25% (3/12) were hUPDs missed by standard AOH analysis of exome. Prenatally, the pipeline resolved 57.1% (4/7; 95% CI: 18.4%-90.1%) of discordant NIPT cases, inferring trisomy rescue and confined placental mosaicism that explained the associated FGR. Postnatally, it unmasked 8 UPD events associated with imprinting disorders for pediatric cases. CONCLUSION: MIE analysis of existing trio-ES data effectively captures hUPDs missed by conventional AOH analysis. Routine integration of this pipeline resolves discordant NIPT results, explains FGR, and enables comprehensive UPD detection.