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Advancing precision care in pregnancy through a treatable fetal findings list

Prenatal Genetics
  • Primary Categories:
    • Prenatal Genetics
  • Secondary Categories:
    • Prenatal Genetics
Introduction:
The use of genomic sequencing (GS) for prenatal diagnosis of fetuses with sonographic abnormalities has grown tremendously over the past decade. Fetal GS offers an opportunity to identify incidental genomic variants that are unrelated to the presenting fetal phenotype but may be relevant to fetal and newborn health. There are currently no guidelines for reporting incidental findings from fetal GS. In the United States, postnatal GS is recommended to include a list of “secondary finding” genes (ACMG SF v3.2) that are associated with disorders for which surveillance or treatment can reduce morbidity and mortality. The genes on ACMG SF v3.2 predominantly cause adult-onset disorders. Importantly, many genetic disorders with fetal and infantile onset are also actionable and treatable. Prenatal testing offers an opportunity to diagnose the fetus and begin treating prenatal- and neonatal-onset disease at the optimal time. We therefore propose a “fetal treatable findings list,” which can be offered to pregnant patients undergoing fetal GS or eventually, as a standalone prenatal cell-free DNA screening tool.



 

Methods:
We conducted an integrative review and synthesized the potential benefits, limitations, and risks to determine which genes and conditions should be screened for prenatally to confer maximal benefit on neonatal health. In this integrative review, we proposed criteria for a fetal findings gene list by identifying genetic disorders with clinically available or emerging fetal therapies, and those for which clinical detection in the first week of life might lead to improved outcomes. Through extensive literature review and input from content experts we created two lists: genetic disorders with available or experimental in utero therapies and genetic disorders for which prenatal diagnosis could plausibly improve outcomes by permitting treatment in the first week of life. We also created a list of future candidate genetic disorders with in utero therapies under investigation in preclinical animal models.

Results:
We identified 53 genes/conditions with in utero fetal therapies in clinical trials and case reports. We identified 267 genes associated with disorders with clinically available therapies that could be applied in the first week of life. Twenty-five of the 267 genes are also listed on the fetal therapies list. We identified 17 genes associated with disorders with experimental in utero fetal therapies in preclinical animal models.



 

Conclusion:
As access to fetal GS grows and the capabilities of cell-free DNA sequencing advance, the field of prenatal genetic diagnosis will continue to expand. The implementation of a treatable fetal findings list has the potential to enhance the autonomy of pregnant patients and improve the health of infants with rare diseases. Although challenges remain regarding the equitable implementation of fetal GS, a treatable fetal findings list could currently be offered to individuals who are undergoing fetal GS, and eventually may form the basis of a prenatal cell-free DNA screening tool that could be offered to all pregnant patients.

 

 

Agenda

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