An Israeli couple, after losing two babies just two weeks after their individual births, have finally given birth to a healthy baby – thanks to an innovative approach taken by Israeli doctors using genetic testing.
The Jewish couple, aged 23 and 24, were devastated when they gave birth to a baby boy who died two weeks after delivery. Then, after a second pregnancy a year later, their second baby boy also died at the age of two weeks.
The first infant suffered respiratory failure in the first hours of his short life and was put on an ECMO machine, which takes over for the lungs and heart. The nightmare repeated itself when a year later, another son was born. Respiratory failure was again diagnosed a few hours after birth and the newborn was attached to an ECMO machine, which also failed to save him.
Desperate to have a healthy baby, the couple – Yafit and Haim Yifrah – turned to Prof. Gheona Altarescu, head of the pre-implantation genetic diagnosis (PGD) unit at Jerusalem’s Shaare Zedek Medical Center (SZMC) and one of the world’s leading experts in the procedure. PGD is a reproductive technology used with an in-vitro-fertilization cycle for diagnosis of genetic disease, removing one cell within the embryo’s first five days to ensure it is normal before implanting it.
“Despite everything, we couldn’t find a clear connection between the mutation in TBX4 and the cause of babies’ deaths.”
Prof. Gehona Altarescu
A genetic mutation discovered
Altarescu conducted genetic screening of the deceased sons and found a mutation in the TBX4 gene that may cause lung disease – but the mutation was also found in the father, who is completely healthy. It turned out that both the father’s brothers and his mother – also healthy – had the same genetic alteration. The geneticists and the parents feared that if a PGD was made that indicated the need for a change in TBX4 – where there is no connection between it and the lung disease – a newborn with the same severe disease could still be born, the professor explained.
THE SHAARE ZEDEK geneticist contacted Prof. Pawel Stankiewicz of the Department of Molecular and Human Genetics at Baylor University College of Medicine in Houston, Texas, where he researches lung disorders. Advanced genetic tests were performed on all members of the nuclear family and samples were sent to Altarescu’s laboratory for a genomic analysis. Those analyses found that the mother had a genetic defect on the same chromosome as the TBX4 gene but that it was located tens of thousands of genetic letters away.
This mutation found in the mother was shown to interfere with TBX4 expression. It was only the combination of the mutation in TBX4 in the father together with the change in the neighboring gene in the mother that led to the fatal disease in both infants.
This amazing discovery led to a genetic breakthrough at SZMC’s Medical Genetics Institute that will help prevent 30% to 40% of cases of this disease and prevent the deaths of such babies all around the world.
The unique TBX4 mutation is not included in common tests, as it involves two genes that are seemingly unrelated and at significant distances from each other but that can “talk to” and influence each other.
In advanced methods, the single gene change in both spouses and in the pre-implantation diagnosis and in-vitro fertilization process was finally born at a good time for the healthy spouses.
YAFIT UNDERWENT the removal of ova that were fertilized by Haim’s sperm to produce embryos. They were analyzed at Altarescu’s lab, and healthy embryos without the mutation were selected for implantation, which finally resulted in the recent birth of a healthy baby girl. This was accomplished thanks to efforts by Prof. Talia Eldar Geva of the IVF unit and Dr. Revital Arbel, a senior SZMC gynecologist.
“Although changes in the TBX4 gene may cause lung disease of varying severity, it was not possible to explain how the mutation we found caused such severe disease,” said the hospital’s PGD expert. “Despite everything, we couldn’t find a clear connection between the mutation in TBX4 and the cause of the babies’ deaths."
The study, she continued, "teaches us about a link between genes and genetic regions that were not necessarily known to be related to or to influence each other. This is another step in the field of genetics. The concept of some genes affecting other genes is a new concept. In the future, we will be able to better understand this complex relationship and find many more treatments for diseases besides preventing them using PGD.”
Today, a new field of treatment is gaining momentum that is based on silencing mutations in the gene that causes diseases.
“In this field, drugs have been developed for hypertension, high levels of harmful cholesterol and heart disease," Altarescu said. "In the future, it will be possible to develop drugs for a wide range of diseases in toddlers and to prevent serious illness and death.”
THE HAPPY new mother recounted the traumatic experience of losing two babies and her fears of getting pregnant again.
“We underwent all the required tests and none of them came up with a solution," Yafit Yifrah said. "Dr. Arbel, who was with me from the beginning of the process, came back and claimed I should meet Prof. Altarescu after the death of my second baby. I realized that this is our last chance to have healthy offspring and that we must do everything to make it happen.”
When she got pregnant, she immediately called Arbel and Altarescu, who were present at the birth at Shaare Zedek. When the baby girl was born healthy and breathed perfectly normally, “I breathed a sigh of relief and cried from excitement – and the staff cried along with me,” Yafit said.
Prof. Efrat Levy-Lahad, director of the hospital’s Medical Genetics Institute, concluded that "the tools for genetic diagnosis in Israel today are groundbreaking, and yet we are [just] at the beginning of fully understanding the genetic map. Any such discovery is a milestone. We are pleased with the results of our extensive research activities and the development of PGD that makes possible a healthy life for thousands of children.”