Rare MGRN1 gene variant tied to fetal heart malformations

The Human Genetics Research Group of the University of Tartu Faculty of Medicine has identified a gene whose defect may cause congenital heart malformations in the fetus. The MGRN1 gene has not previously been associated with early human development or with any disease. The discovery will help doctors better recognize similar cases in the future and improve the counseling and treatment offered to affected families.

The finding emerged during the genetic investigation of one Estonian family. The family had experienced two pregnancies that were terminated after ultrasound scans revealed severe structural anomalies in the fetuses. Pathological examination in both cases demonstrated congenital heart malformations, and in one fetus, abnormal positioning of internal organs.

At the same time, the family already had two healthy children. Therefore, the family’s genetic material reached the laboratory of Laura Kasak, Lecturer of Human Genetics at the University of Tartu.

The article describing the new finding, “MGRN1 is linked to recessive heart and laterality defects: the first genotype–phenotype report in humans,” is published in the journal Journal of Medical Genetics.

“In clinical practice, the fetuses and the parents had undergone genetic testing, but nothing unusual had been detected. This is not surprising, as the tests focused on known associations,” Kasak explained. “So we began searching for the cause of the anomalies elsewhere.”

Because both parents were healthy yet the fetuses had similar developmental anomalies, Kasak suspected an autosomal recessive genetic condition. This means that the disorder manifests only when the child inherits a pathogenic variant from both parents.

The analysis confirmed that both parents carry a rare recessive variant of the MGRN1 gene, which has not been studied in depth because it has never been linked to any specific human disorder. “It is even rarer for two carriers of the same variant to meet,” Kasak noted.

The researchers’ hypothesis was further supported by genetic testing of the healthy children in the family: none of them carried two defective copies of the gene. Additional confirmation came from mouse-model studies, which showed that a defective MGRN1 gene leads to similar malformations and pregnancy loss in rodents.

The discovery elicited mixed feelings among the researchers. “On one hand, it is very difficult emotionally, because you feel for the family and think how unfair such a chance event is. On the other hand, you are grateful for the scientific discovery, which may contribute to the early identification of similar situations in the future,” Kasak reflected.

According to Kasak, further investigation of the gene and additional experiments are needed. The first priority, however, is to share the discovery with the scientific community so that others can recognize the association and expand on the opportunities it offers.