Casual Genetic Variants In Stillbirth

Stillbirth is defined as fetal death in utero at >= 20 weeks' gestation. It makes up 60% of all perinatal deaths, but the cause remains unknown in 25% to 60% of cases. Previous studies have demonstrated that exome sequencing is useful in identifying a diagnosis in unexplained childhood disorders (in 20%-30% of such cases) and fetal structural anomalies (in approximately 10%-20% of such cases). Therefore, these researchers aimed to study the diagnostic yield of exome sequencing in stillbirth cases.This study evaluated 246 cases of stillbirth through a multicenter case-control study in a diverse population within the United States. The study included fetuses at >= 20 weeks' gestation from the Stillbirth Collaborative Research Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Among these fetuses, the most common cause of death was an obstetrical condition followed by placental abnormalities, fetal structural abnormalities, infection, umbilical cord abnormalities, hypertensive disorders, and other maternal medical conditions. Exome sequencing was performed at the Institute for Genomic Medicine at Columbia University and was limited to 18,653 protein-coding genes. Overall, 246 cases were screened for molecular diagnoses using the guidelines set forth by the American College ofMedical Genetics and Genomics. Two sets ofmolecular diagnoses were identified in 221 genes previously reported in association with stillbirth as well as in genes that were considered strong candidates. Genes were stratified in relation to the level of depletion of functional variation (designated as "intolerant" to variation) and the loss-of-function observed-to-expected upper boundary fraction value.In all, 953 potential participants were identified, and 663 were enrolled in the initial stillbirth study. Of these 663 patients, 560 consented to partial or complete postmortem fetal examination; 314 were excluded because of inadequate DNA samples or a previously well-defined cause of stillbirth. Therefore, 246 cases were included for exome sequencing. A molecular diagnosis was made in 9 of the 246 included cases (3.7%) across 7 genes. An additional 6 cases (2.4%) had a molecular diagnosis made in a strong candidate gene, giving a cumulative diagnostic yield from exome sequencing of 6.1%, with 15 of 246 stillbirth cases leading to a molecular diagnosis. Of these 15 cases, 6 (40.0%) had a multisystem developmental disorder, 5 (33.3%) had an isolated cardiac disorder, and the remainder had a disorder primarily affecting the kidney. In 6 cases (2.4%), there was a "suggestive" genotype, and 21 cases (8.5%) had a probable molecular diagnosis from exome sequencing. The intolerant genes were identified as having a loss-of-function observed-to-expected upper boundary fraction of =0.239. In this study, there were more loss-of-function variants in genes that are intolerant to variation in the human population (odds ratio, 2.15; 95% confidence interval, 1.46-3.06). Approximately 7.2% of stillbirth cases were likely caused by loss-offunction variants in intolerant genes. Furthermore, these variants weremore often located in genes without an existing OMIM disease association (odds ratio, 2.22; 95% confidence interval, 1.41-3.34). The researchers also estimated that approximately 5.5% of stillbirth cases were likely attributed to loss-of-function variants in novel disease genes.The authors conclude that their study demonstrates the clinical utility of exome sequencing in cases of stillbirth, wherein exome sequencing can identify variants in genes that may lead to stillbirth. However, the causes of stillbirth are still predominantly unknown. Further research is necessary to analyze more stillbirth cases and will likely give rise to additional associated genes.