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.