NEW YORK – A fetal genome sequencing actionable findings list could improve fetal diagnosis and perinatal outcomes, and grant expectant patients greater autonomy over how to proceed with their pregnancy, argue a group of physicians and researchers specializing in pediatric medicine.
In a preprint currently undergoing peer review and available on MedRxiv, the investigators propose a set of criteria for establishing an actionable fetal findings list based on the American College of Medical Genetics' secondary findings list.
Nina Gold, director of prenatal medical genetics at Massachusetts General Hospital and the study's senior and corresponding author, said that the genes on the ACMG secondary findings list typically relate to adult-onset disorders. At present, the International Society of Prenatal Diagnosis recommends that karyotyping and microarray-based testing should be offered to all pregnant patients, whereas exome sequencing should be reserved only for cases in which fetal anomalies are present.
As fetal exome sequencing has become both more advanced and commonplace, however, she and her colleagues began to question whether these findings could be extended to include genes related to perinatal onset disorders that can be treated either before or immediately after birth.
"We had a patient [for example], who found out through carrier screening, that she was carrying a fetus with cobalamin C deficiency, which is a rare inherited metabolic disorder," Gold said. In the case of early-onset patients, this disorder can cause severe neurological, ocular, hematological, renal, gastrointestinal, cardiac, and pulmonary complications. The treatment, however, can be quite simple and effective if done early enough.
"We treated the mom with high-dose [vitamin] B12 and the baby didn't even flag as being considered for the disorder on the newborn screen because when he was born, the symptoms were so mild, and at one year he's doing developmentally great," Gold said.
Gold and her colleagues identified 53 disorders with in utero fetal therapies either in clinical trials or described in case reports, and 267 disorders with clinically available therapies that can be administered within the first week after birth.
Establishing an actionable fetal genetic findings list is important for a number of reasons, Gold said.
First, findings often go unreported simply because there are no current standards for which genes to investigate in the fetal setting. Additionally, she said, newborn screening results often arrive too late to benefit the baby.
"The current secondary findings panel is not recommended for use outside of adults and children," Gold said, and specifically not in the prenatal setting. "We're suggesting that maybe there are some [genes] that do belong on a [fetal] secondary findings panel."
Secondly, an actionable fetal findings list could help reduce some of the disparities in access to carrier screening.
Most of these disorders on Gold's proposed list do not present with ultrasound findings, meaning that the benefits of prenatal therapy can only be realized by patients with a known family history of disease or who have undergone carrier screening. However, few countries have a uniform approach to carrier screening. Within the US, access to specialist care, insurance coverage, and a patient's race all contribute to the range of barriers people can face in receiving carrier screening.
"The implementation of a treatable findings panel for fetal genomic sequencing would allow additional pregnant patients who may not have undergone expanded carrier screening to receive information about care options," Gold said.
Ronald Wapner, director of reproductive genetics at Columbia University's Irving Medical Center, called Gold's review an "important article that raises [the] question of what we should be screening and testing for during pregnancy."
"Many disorders are best diagnosed prenatally since care delayed until birth is frequently suboptimal," he said.
The 53 disorders with in utero fetal therapies include Hurler syndrome, infantile-onset Pompe disease, and long QT syndrome. The more than 200 disorders with available therapies include adrenal hypoplasia, infantile diabetes mellitus, and STXBP1-related neonatal epilepsy. Some disorders, such as infantile-onset Pompe disease, have genes in both lists.
Criteria for inclusion on these lists included consideration of risk-benefit ratio, such as any fetal intervention being tolerable and showing the potential for efficacy without causing undue risk to either the fetus or mother. This rules out, for example, fetal interventions that carry a risk of preterm delivery or premature rupture of membranes.
"We chose things that had a relatively safe fetal and maternal [safety] profile," Gold said.
Other criteria included an association with critical or chronic childhood illness and, at least for the most part, that the condition does not lead to structural anomalies that would be seen by sonography.
Wapner said that fetal and neonatal treatments should be seen as important options to be offered to patients.
"These options will continue to expand as gene therapies and gene editing are integrated into prenatal care," he said.
Ingrid Holm, a professor of pediatrics at Harvard University who was not part of the study, praised it for addressing the question of how sequencing will increasingly be used to address prenatal care, noting that it will form something of a "moving target," as it would need to be continuously updated.
"I would like to see a consolidated approach to prenatal testing using genomic sequencing," Holm said, "potentially in the form of guidelines from professional societies, such as [the American College of Obstetricians and Gynecologists] and ACMG working together."
Gold herself serves on the ACMG working group on prenatal sequencing and said that the proposed list will be a topic of discussion at upcoming meetings.
Gold's study is currently undergoing peer review in "a journal that promises a pretty quick turnaround," and she hopes to see it published sometime in November.
"We hope this [helps] level the playing field," Gold said.