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    The promise and peril of new prenatal diagnostic technologies

     

    Take-home message

    We need to develop simple, clear strategies for offering prenatal and carrier testing that will benefit couples choosing to avail themselves of such studies. For the present we must better understand the advantages of both cfDNA and standard aneuploidy testing and develop algorithms that optimize each modality’s diagnostic strengths while minimizing costs. However, in the relatively near future, commercially available cfDNA diagnostic options are likely to vastly expand. When that occurs, we must develop a coherent set of cfDNA diagnostic options readily understandable by patients and readily implementable by practitioners.

    One approach would be to offer a series of cfDNA testing sets of increasing complexity while ensuring that couples are fully informed of the scope and limitations of such screening. For example, patients might choose from a menu of cfDNA diagnostic offerings that include a basic trisomy screen, an expanded screen that includes a search for microdeletions and microduplications of known and clinically significant phenotype, or one that includes all these elements plus a screen for discrete single-gene conditions with severe phenotypes and high penetrance and expressivity. These tests could have variable pricing with payers determining the cost-effectiveness of coverage and market forces establishing residual pricing. Professional societies would need to collaborate to establish when a given condition should be added to the diagnostic paradigm. Couples would need to waive their right to access data of uncertain or trivial clinical significance. For patients in whom a cfDNA assay cannot be performed for technical reasons, consideration should be given to offering reflex standard testing or even invasive testing with chromosomal microarray analysis, depending on the parents’ wishes.

    Expanded carrier screening also requires a standardized and parsimonious approach. A recent joint statement by American College of Obstetricians and Gynecologists, the American College of Medical Genetics and Genomics, the National Society of Genetic Counselors, the Perinatal Quality Foundation, and the Society for Maternal-Fetal Medicine outlines a cogent and practical set of principles for such testing.5 These include the necessary elements of pretest informed consent (eg, that risk assessment depends on an accurate knowledge of paternity, that a negative screen does not eliminate risk, and that screens for autosomal-dominant conditions may reveal prognostic information about them for which little can be done). Post-test counseling must also be available as well as a plan for sequential testing of the other parent for a given autosomal-recessive condition and information about prenatal diagnostic testing if so desired.

    The Joint Statement authors also opine about which types of disorders should be tested for, such as those resulting in cognitive disability, those with substantial effects on quality of life, or those for which prenatal or obstetric interventions may improve outcomes. The authors stipulate that practitioners should have the freedom to not recommend screening for conditions with a highly variable adult phenotype (eg, alpha-1-antitrypisin deficiency) or conditions with low penetrance and expressivity (eg, Factor V Leiden or MTHFR mutations). The Statement also provides recommendations about which results should be reported (eg, reporting only those variants with clear phenotypes and the highest likelihood of being pathogenic).

    We are at the dawn of a new age of prenatal testing that holds promise to provide expectant couples with important information about their fetus’ genetic heath. However, misapplication of these technologies will lead to stress, confusion, high costs and, potentially, social instability. Thus, we will need to find a practical equipoise amongst our obligations to: respect parental autonomy, personal choice, and individual freedom; ensure beneficence toward the fetus; and ensure a genetically diverse, just, and equitable society.

     

    Charles J. Lockwood, MD, MHCM
    Dr. Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South ...

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