Embryonic lethal genetic variants and chromosomally normal pregnancy loss.

Objective: To examine whether rare damaging genetic variants are associated with chromosomally normal pregnancy loss and estimate the magnitude of the association.

Design: Case-control.

Setting: Cases were derived from a consecutive series of karyotyped losses at one New Jersey hospital. Controls were derived from the National Database for Autism Research.

Patient(s): Cases comprised 19 chromosomally normal loss conceptus-parent trios. Controls comprised 547 unaffected siblings of autism case-parent trios.

Intervention(s): None.

Main Outcome Measure(s): The rate of damaging variants in the exome (loss of function and missense-damaging) and the proportions of probands with at least one such variant among cases vs. controls.

Results: The proportions of probands with at least one rare damaging variant were 36.8% among cases and 22.9% among controls (odds ratio, 2.0; 99% confidence interval, 0.5-7.3). No case had a variant in a known fetal anomaly gene. The proportion with variants in possibly embryonic lethal genes increased in case probands (odds ratio, 14.5; 99% confidence interval, 1.5-89.7); variants occurred in BAZ1A, FBN2, and TIMP2.

Conclusion(s): Rare genetic variants in the conceptus may be a cause of chromosomally normal pregnancy loss. A larger sample is needed to estimate the magnitude of the association with precision and identify relevant biologic pathways.