State-of-the-art genetic testing shows promise in determining the cause of prenatal death and likelihood of a recurrence in future pregnancies, according to Australian researchers. Their results, with whole exome sequencing (WES) and whole genome sequencing (WGS) were published in Human Reproduction.
“The cause of pregnancy loss and perinatal death remains unexplained in at least 25% of cases, despite a high perinatal autopsy rate in countries such as the United States and Australia,” said Christopher Barnett, MBBS, FRACP, FCCMG, a consultant clinical geneticist and head of the Paediatric and Reproductive Genetics Unit at the Women's and Children's Hospital in North Adelaide, Australia.“The most common factor contributing to perinatal death is congenital abnormalities.”
Presenting at the European Society of Human Genetics conference (ESHG), Dr. Barnett described outcomes with WES and WGS as a way to identify genetic causes of fetal/newborn abnormalities that result in termination of pregnancy, death in utero or in the newborn period. Using data from 43 families referred to the genetics unit, where samples were available from both parents and the fetus (the prospective cohort), and 60 from stored autopsy samples from the fetus or newborn (the retrospective cohort), researchers were able to uncover an underlying genetic cause in 23% of the prospective cohort, and have found a single promising candidate in a further 26%.
“Genomics has the potential to unlock the cause of complex congenital abnormalities in 50% to 60% of cases,” Dr. Barnett told Contemporary OB/GYN.
The study’s yield appears to be higher in this population of affected fetuses/newborns than it is in children with congenital abnormalities, according to Dr. Barnett. “Our hypothesis is that the more severe abnormalities that present in utero are more likely to be genetic,” he said.
An accurate diagnosis enables families to access genetic testing early in their next pregnancy to determine whether they are carrying an affected pregnancy. “The risk of carrying an affected pregnancy may be as high as 1 in 2, depending on the form of inheritance,” Dr. Barnett said.
Furthermore, genetic testing enables access to preimplantation genetic diagnosis. “This is the situation where a couple's Day 5 embryo is biopsied and tested for the previously diagnosed genetic disorder in the family,” Dr. Barnett said. “A healthy embryo without the genetic disease is then transferred and the pregnancy can continue normally.”
Dr. Barnett said couples who have experienced a pregnancy complicated by a serious genetic problem, in which a clear diagnosis has not been made, are less likely to have more children than couples with a precise diagnosis. “Uncertainty is a powerful deterrent,” he said.
Dr. Barnett is encouraged by the uptake of his study. “Parents want answers,” he said. “However, we also counsel families about the possibility of incidental findings and variants of unknown significance, which can be obstacles.”
For instance, it is possible that a definite mutation in a deceased fetus has implications for the parent’s own health. “A good example of this would be a mutation in a cardiomyopathy gene,” Dr. Barnett said. “Although it may have presented lethally in a fetus, it could be carried by a parent at risk of developing cardiomyopathy in their 40s or 50s perhaps.”
Nonetheless, Dr. Barnett envisions genetic testing as the gold standard in perinatal autopsy: standard anatomical autopsy plus trio whole genome or whole exome sequencing.
Dr. Barnett reports no relevant financial disclosures.