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Gene discovery in idiopathic preterm delivery or uterine atony
Abstract Number: F-39
Abstract Type: Original Research
Preterm labor and delivery (PTD),(1,2) labor duration,(3) post-dates delivery (4) and uterine atony (UA) are believed to be in part genetic; however, no genes have been identified that specifically predict PTD (‘uterine hypercontractility’) or UA (‘uterine hypocontractility’). Gene identification has proven challenging because of extreme difficulty identifying the subset of women with idiopathic PTD and UA and the challenges controlling for the many obstetric factors that may confound the diagnosis. We defined stringent criteria for identifying idiopathic PTD and UA, report on the results of exome sequencing, and use this foundational work to build a much larger cohort to drive gene discovery.
Using a cohort of 1969 women with obstetric and neonatal data and available DNA, we screened cases with PTD or UA. PTD was defined as delivery <37wks (252 days) with no chorioamnionitis, preeclampsia, uterine rupture, cord prolapse, placental abruption, fetal anomaly, in a singleton pregnancy with ≥1 episode of preterm labor; our search yielded N=13. UA was defined by 3 consecutive criteria: induction of labor > 40wks (280 days, post-dates), failure of labor (without non-reassuring fetal status) requiring an intrapartum cesarean delivery, and intraoperative uterine atony requiring 2nd-line uterotonics; our search yielded N=4.
Exome sequencing (Roche/Nimblegen SeqCap EZ V3.0) was performed on the 13 PTD and 4 UA cases. Following alignment and variant calling, genes previously implicated in abnormal deliveries were screened for low frequency candidate variants. Comprehensive gene-level association testing was also performed comparing cases to ~5000 ethnically-matched population controls looking for enrichment of rare, putatively protein-disrupting mutations.
No genome-wide significant signals were detected at the gene-level in this small retrospectively-collected cohort; however, through by evaluating ~180 genes previously studied in the context of pregnancy (PTD, labor duration or postdates delivery), we identified one rare missense allele in IGF1R in one PTD case (NM_000875.3:c.1633G>A;p.(Gly545Ser). The IGF1R encodes insulin-like growth factor receptor 1, an important protein that may contribute to signaling of the onset of labor, and has been previously implicated in PTD through linkage analyses.(5)
We developed well-defined phenotypic criteria to identify true idiopathic uterine hypo- or hyper-contractility, and report findings from the exome sequencing of selected cases from a large cohort. While the genetic basis remains elusive in this small cohort, we will use this framework to build a much larger prospectively-collected cohort that will likely quickly advance gene discovery and our ability to identify women at high risk for complicated births.
1. BMC Genomics 2016:17:759
2. BJOG 2015:122:1387-94
3. Am J Obstet Gynecol 2012:207:184
4. BMC Med Genet 2010;11:105.
5. PLoS Genet 2011;7:e