NEW YORK – A Columbia University-led team has used a clinical exome sequencing approach to uncover genetic contributors to stillbirth while highlighting what is still to be learned about the genetics of such fetal death cases.
"Our findings establish the diagnostic utility of clinical exome sequencing to evaluate the role of small genomic changes in stillbirth," senior author David Goldstein, director of the Institute for Genomic Medicine at Columbia University Medical Center, and his colleagues wrote in a paper appearing in the New England Journal of Medicine on Wednesday, noting that even after accounting for these new results, "the genetic cause of stillbirth remains largely unknown."
For their study, the researchers did exome sequencing on nearly 250 stillborn cases, uncovering molecular culprits in 15 of those cases. Along with those genetic alterations, which fell in seven known risk genes and half a dozen candidate risk genes, they used a case-control analysis to show that stillbirth tends to correspond to alterations involving genes that are typically averse to loss-of-function changes in the broader population.
"Loss-of-function variants in intolerant genes were concentrated in genes that have been associated with human disease," the authors wrote, noting that those results "differ from those in two post-natal clinical populations that were also evaluated in this study."
While chromosomal alterations in known risk genes appear to explain up to one in five stillborn cases, the team explained, the full range of genetic changes that contribute to fetal death at or beyond 20 weeks of gestation is still being identified, with anywhere from one-quarter to some 60 percent of cases stemming from unknown causes.
"Given the incidence of stillbirth and the presumption of a strong genetic contribution, it is unfortunate that clinical exome sequencing has not been applied more rigorously in this context," the authors wrote, noting that "identification of monogenic disorders that are responsible for stillbirth may facilitate closure and bereavement for families, inform recurrence risk and management in subsequent pregnancies, allow for the avoidance of ineffective and potentially harmful therapies and interventions, and identify novel targets for risk stratification and therapy."
Starting with tissue samples collected through the National Institute of Child Health and Human Development's Stillbirth Collaborative Research Network from fetal death cases that occurred after at least 20 weeks of gestation, researchers at Columbia's Institute for Genomic Medicine did exome sequencing analyses on tissue samples from 246 stillborn cases that could not be explained by well-established risk factors.
When the team searched for pathogenic variants in the protein-coding portions of the genome in those cases, focusing on potential Mendelian genes, it uncovered changes to seven known stillbirth-related genes that appeared to explain nine of the cases. Another six cases were linked to alterations affecting six candidate risk genes.
Half a dozen of the molecularly diagnosed cases appeared to stem form multi-system developmental problems, the researchers reported, while five of the cases involved cardiac disorders. Genes with ties to cardiac function were also overrepresented among the molecular diagnoses done with the exome data.
The team also compared exome sequence data for 241 stillbirth cases involving loss-of-function alterations to data from more than 7,200 population controls, demonstrating that loss-of-function changes in genes that are typically considered intolerant to such mutations were more common in the stillbirth cases than they were in the population as a whole.
"Exome sequencing analysis of larger, independent stillbirth cohorts would test the validity of our results and almost certainly uncover additional genes that are associated with stillbirth," the authors noted. "We anticipate that the identification of specific genes and variants will further improve our understanding of the pathways leading to stillbirth and improve the counseling of affected families."