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

Systematic Mendelian inheritance error analysis of trio exome data, quantified by a biparental inheritance percentage, to detect uniparental disomies including heterodisomies invisible to absence-of-heterozygosity analysis.

Uniparental disomy, particularly heterodisomy, is an underdiagnosed cause of fetal growth restriction and discordant noninvasive prenatal testing, because conventional absence-of-heterozygosity analysis frequently misses it. The authors validated a systematic Mendelian inheritance error pipeline on trio exome data in a two-stage study covering 1,948 parent-offspring trios: a retrospective cohort (n = 992) established the quantitative biparental inheritance percentage threshold, which was then applied prospectively (n = 956) to discordant noninvasive prenatal testing and unexplained fetal growth restriction, with orthogonal confirmation by methylation or short-tandem repeat analysis. Using a biparental inheritance percentage below 0.7, the pipeline identified 12 clinically significant uniparental disomy events, of which 25% (3/12) were heterodisomies missed by standard exome absence-of-heterozygosity analysis. Prenatally, it resolved 57.1% (4/7; 95% CI 18.4% to 90.1%) of discordant noninvasive prenatal testing cases, documenting trisomy rescue and confined placental mosaicism that explained the associated growth restriction; postnatally, it unmasked 8 uniparental disomy events associated with imprinting disorders.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is the kind of work laboratories like: no additional data to generate, detection relies on re-reading trio exomes already performed, and it recovers precisely the blind spot of heterozygosity-based analysis, namely heterodisomies. Caution concerns the clinical numbers: 12 events, and above all 4 of 7 resolved prenatal discordances, yield a confidence interval spanning 18% to 90%, which supports a feasibility conclusion but not a resolution rate to quote to a couple. Two transposition requirements should not be forgotten: the approach presupposes trio exome sequencing, so it does not apply to singleton proband testing, and any suspected disomy must keep its methylation or short-tandem repeat confirmation before reporting.

Analysis by Dr Thibaut Benquey