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.