NEW YORK – Researchers from Duke University, Harvard Medical School, Massachusetts General Brigham, and elsewhere have proposed a "treatable fetal findings" gene list for reporting secondary findings from diagnostic fetal genome sequencing, where the current secondary findings list from the American College of Medical Genetics and Genomics (ACMG) does not apply. Potentially, such a list could be used as part of a cell-free fetal screening test in the future.
In a review article published in the American Journal of Human Genetics on Wednesday, the team identified 296 genes that are associated with disorders that have therapeutic interventions either in utero or in the first week of life.
"We suggest that the disorders for which there have been successful treatments reported in individual human cases, disorders with fetal interventions that are currently in clinical trials, and disorders for which treatment in the first week of life may improve outcomes should be considered for a treatable fetal findings list," the authors wrote.
Nina Gold, director of prenatal medical genetics at Massachusetts General Hospital and the senior author of the article, said fetal exome sequencing, which is used to diagnose fetuses that have abnormalities on an ultrasound, is becoming more common. Such ultrasound findings occur in an estimated 2 percent to 3 percent of pregnancies. The suggested gene list for secondary findings could provide relevant, actionable information during pregnancy on the risk of the fetus developing treatable disorders, she said.
Eventually, these genes could be assessed in all pregnancies through an optional cell-free fetal DNA screening test, the authors wrote.
Such a test could also overcome the shortcomings of carrier screening, they added. Most countries lack a uniform approach to carrier screening, the panel contents vary widely, and none of those tests can be used to identify de novo disorders of the fetus, they wrote.
Gold said her team's gene list has some overlap with the US Department of Health and Human Services' Recommended Uniform Screening Panel, which the federal government recommends states include in their newborn screening programs. However, she said that a baby can already be in the NICU for treatment of the metabolic disorder galactosemia, for example, when those newborn screening test results come in, and making a diagnosis before birth would be helpful.
Treating galactosemia or maple syrup urine disease, for example, requires special diets, and doctors can intervene sooner if prenatal screening shows an elevated risk, she said. Other diseases, such as ornithine transcarbamylase (OTC) deficiency, are not included in the RUSP, and newborn boys with the most severe form of the disease can accumulate high levels of ammonia in their blood within the first day or two of life.
"Genomic newborn screening programs have been reluctant to include OTC even though it's very treatable because they think it will have presented by the time results return," she said.
If newborn screening testing does not provide results quickly enough to act, "we need to shift the timeline of when we're testing," she said.
The article includes other examples of interventions that can prevent adverse outcomes in the first week of life, for example, for infants with biotin-thiamine responsive basal ganglia disease, arginine vasopressin resistance, and coagulation factor deficiencies. Early results for these could also help healthcare providers avoid interventions that could lead to adverse outcomes, such as administering sucrose-sweetened medicines to infants with congenital sucrase-isomaltase deficiency or providing phototherapy to infants with erythropoietic protoporphyria.
While newborn screening has reduced illnesses and deaths among babies with severe combined immunodeficiency (SCID), earlier identification through genomic screening could help parents receive referrals for bone marrow transplant evaluation and initiate human leukocyte antigen (HLA) typing for donor matching, they wrote.
They cautioned, though, that offering expanded prenatal screening risks overwhelming patients with information. Gold said she counsels pregnant patients and is aware that additional information on disease risks can cause undue stress.
Susan Klugman, ACMG's former president, said in an email that ACMG has a group that is reviewing the current secondary findings "and will need to consider whether or not a second group should analyze fetal secondary findings."
She added that the reports and clinical trials of therapeutic interventions in fetuses and newborns "need to each be examined critically as many of the conclusions are not yet published and many of the trials involve only one subject."
Klugman noted that diagnostic fetal genome sequencing is gaining acceptance, especially in response to ultrasound anomalies, but that sequencing has not yet become the standard of care and is not covered by most insurance providers.
Gold said the gene list could be refined through workgroups and content experts to determine which targets would provide the greatest results for patients. Patients may not always appreciate the complexity, nuances, and uncertainty of test results, but they could use the information on available treatments to help them to make more informed choices.
"When someone has a fetus with an anomaly or a genetic diagnosis, they may be at a crossroads between continuing the pregnancy and considering termination," she said. "But we're presenting, hopefully, a complete list of disorders for which there is a third option, which would be offering some sort of treatment if one wants to continue the pregnancy but wants to try to ameliorate the symptoms of the associated disease."
Gold said she and her fellow researchers hope that experts in genetics, obstetrics, and prenatal health will help develop an optimized list of genes that would be appropriate for prenatal screening and that clinicians will help to establish how the panel could be implemented in the clinic.