Impact Case Study

Uncovering the elusive causes of fetal death

Molecular autopsy reveals gene variants not previously associated with pregnancy loss and diseases. 

20 September 2018

By analysing fetal DNA, researchers at King Faisal Specialist Hospital and Research Center and the Saudi Human Genome Program at King Abdulaziz City for Science and Technology in Saudi Arabia have investigated possible genetic causes of unexplained pregnancy losses, and revealed mutations in genes not previously linked to human diseases. This could help clarify which genes are essential for early human development. 

The study included 44 families, mostly consanguineous. They had experienced one or more intrauterine deaths, lethal fetal malformations, or an abnormal accumulation of fluid in two or more fetal body areas, known as nonimmune hydrops fetalis. After excluding major chromosomal abnormalities as causes of miscarriage or stillbirth, the DNA tests were conducted on samples from placental tissue, amniotic fluid, or the umbilical blood. DNA testing was also performed on couples who had experienced previous intrauterine fetal deaths or lethal nonimmune hydrops fetalis but did not have available samples from those pregnancies.

The analysis was based on exome sequencing — a technique used to select and sequence the parts of the genome that encode proteins. Through this molecular autopsy, the researchers could identify possibly harmful variations in gene sequences and suggest a clinical interpretation. 

Gene variants that could potentially explain intrauterine death were identified in 50 percent, while variants of unknown significance were found in a further 34 percent of the families. Some variants were already known to cause pregnancy loss. Others were known to typically cause severe paediatric diseases, but not embryonic death. 

Another one third of the identified variants were in genes that have been shown to cause death in animal models, but with no established role in human diseases. This last subset involved 13 genes, including a mutation that leads to brain and joint defects, and another that results in a disease characterized by malformation of the brain and kidneys. The researchers found variants in genes encoding proteins with essential functions, like the DNA repair protein FEN1, which is known to cause embryonic lethality in mice but not humans. 

Currently, the causes of most stillbirths are unknown. Post-mortem examination of fetuses is rarely conducted due to grief, or cultural reasons. The authors of the study found that molecular autopsy is more likely to be accepted by parents. This technique could help with more accurate genetic counselling, and to guide the diagnosis when the abnormalities are not visible with imaging studies, or are not specific to a unique disease.


  1. Shamseldin, H. E., Kurdi, W., Almusafri, F., Alnemer, M., Alkaff, A., et al. Molecular autopsy in maternal–fetal medicine. Genetics in Medicine20(4), 420 (2018). | article