Initial findings from Tufts Medical Center study show promise in diagnosing infants with rare genetic conditions

Tufts Medical Center is pictured on Aug. 28, 2014. Nicholas Pfosi / The Tufts Daily Archives

In an effort to minimize the amount of time required to diagnose newborns with rare genetic conditions, researchers at the Tufts Medical Center launched the Genomic Medicine for Ill Neonates and Infants (GEMINI) study in 2019. The study, which published its initial findings on Feb. 15, uses a targeted genomic sequencing platform to screen for over 1,700 genes that may be linked with genetic abnormalities.

Some infants are born with rare genetic conditions that can negatively influence their health and present life-threatening complications during the first few weeks of life. In order to treat these newborns, clinicians are given the often difficult task of performing diagnostic genetic tests to find the root of the problem.

However, diagnosing rare genetic conditions can be a long and arduous process. Too often, infants go either misdiagnosed or undiagnosed. Even when an accurate diagnosis does occur, it typically takes years for clinicians to pinpoint the specific site of the genetic abnormality. For newborns that present with urgent conditions — such as seizures — a lengthy diagnostic process may not be an option, as it could potentially result in the infant’s death.

Whereas these older forms of testing for genetic conditions can take years, the GEMINI study is able to provide answers within a week. In the most urgent cases, clinicians can use the genomic sequence to diagnose infants within 72 hours.

The study, which to date has enrolled over 250 infants suspected of having genetic conditions, has already saved lives. Dr. Jill Maron and Dr. Jonathan Davis, who together serve as principal investigators of the study, shared the story of an infant who presented with seizures shortly after birth.

“We were giving this baby very large doses of multiple anti-seizure medications, and we could not control the baby,” Davis, the vice-chair of pediatrics and chief of neonatology at Tufts Children’s Hospital and a professor of pediatrics at Tufts University School of Medicine, said. “So we entered the baby into the study.”

Using GEMINI’s targeted genomic sequencing platform, the researchers were able to diagnose the child with a rare vitamin deficiency, caused by a genetic abnormality, within 48 hours.

“As soon as we gave the baby the active form of the vitamin … seizures stopped immediately,” Davis said. “Within hours, we were taking [the baby] off of all these seizure drugs, and within a day the baby started to wake up.”

Several days later, the infant was able to go home. Davis said that had it not been for the diagnostic technique presented by the study, clinicians would have struggled to find the source of the seizures.

“It’s a very powerful technique,” Davis said. “It’s still early in the process, but that sort of gives you an idea of the power of these techniques to really enhance our abilities to make the right decisions and to treat [diagnoses] in a timely fashion.”

Unfortunately, not all newborns who are diagnosed with a genetic condition survive. A number of the genetic conditions that the GEMINI study screens for are fatal.

“Some cases aren’t always happy endings,” Maron, the executive director of the Mother Infant Research Institute at Tufts Medical Center and professor of pediatrics and obstetrics and gynecology at Tufts University School of Medicine, said. “It works both ways in these studies, where sometimes we can come in and tell the family that [the condition] is fatal … and they can find peace.”

In addition to sequencing the genome of newborns, the GEMINI study offered targeted genomic sequencing to the families of enrolled infants. Maron explained that clinicians can then use the sequencing results to inform parents of the risks of genetic conditions, including fatal ones, in subsequent pregnancies.

“We are able to guide care in the appropriate way and inform future reproductive choices to the family,” Maron said.

The GEMINI study uses a targeted platform to sequence 1,722 specific genes that are known to be associated with genetic conditions. While full genome sequencing has become increasingly accessible over the past decade, Maron explained that there may be cost barriers and ethical concerns that come with sequencing the entire genome of newborns.

“When you sequence the entire genome, you may come across incidental findings, or adult-onset diseases,” Maron said. “Is it okay to uncover that a newborn may have significant heart disease when they’re older, or may have a devastating neurological disorder when they’re older?”

Of the newborns that participated in the interim study, 45% were discovered to have a genetic abnormality. It remains unclear whether the remaining 55% of enrolled infants truly did not have a genetic condition. Maron suggested that current limitations to genomic research may be precluding accurate results for children with undiagnosed genetic conditions.

The study intends to enroll 400 members by its conclusion. Davis predicts that in the long term, GEMINI may have far-reaching benefits in the diagnosis of genetic conditions in newborns.

“This is going to be a revolutionary change in the field of genomics,” Davis said. “It’s going to be a revolutionary change in the way we manage babies as well.”


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