The ACMG's Professional Practice and Guidelines Committee published guidance for referring physicians, laboratory geneticists, genetic counselors, and clinical laboratories in a "points to consider" document on the use of fetal exome sequencing in prenatal diagnosis in Genetics in Medicine, its official journal. The advice is intended to help multidisciplinary professionals at a time of increased use of prenatal testing. Significant fetal anomalies are present in 2% to 4% of pregnancies, and genetic counseling with a review of testing options should be offered in these cases, according to the guidance.
"The prenatal testing strategy and test selection should be individualized and guided by prenatal imaging findings and family history," wrote Kristin Monaghan, PhD, assistant director of whole genome sequencing at genetic testing provider GeneDx, and colleagues.
Prenatal testing techniques include karyotyping, fluorescence in situ hybridization, and chromosomal microarray analysis (CMA), but even with these, "more than half of fetuses with structural anomalies remain without a diagnosis," leaving room for genome sequencing and exome sequencing to assist, the authors noted.
"A genetic diagnosis can assist in determining the fetal prognosis and inform prenatal care, including decisions on reproductive choice, in utero therapy, delivery planning, and neonatal management, potentially decreasing morbidity and mortality," they wrote. "It may also refine the recurrence risk leading to informed genetic counseling where future reproductive options, including preimplantation genetic testing, diagnostic prenatal testing, or consideration of donor gametes could be addressed."
Rapid turnaround essential
The ACMG committee stressed that prenatal exome sequencing testing is time-sensitive and, consequently, to maintain reproductive choice, clinical laboratories must have clearly defined turnaround times.
"Sufficient specimen quantity is required for a rapid turnaround time and ordering providers should be considerate of specimen requirements established by a testing laboratory," the authors wrote.
They noted that in one large prospective study, exome sequencing was useful for diagnosing 10% of fetuses with structural anomalies overall and 19% of fetuses with more than one anomaly. In another prospective study, exome sequencing helped reach a diagnosis of 8.5% of fetuses overall and 15.4% of fetuses with more than one anomaly.
"Both studies demonstrate that [exome sequencing] increases the diagnostic yield in structurally abnormal fetuses by about 8-10% after normal karyotype and CMA results, and the detection rate is strongly correlated with the number of fetal anomalies," the group wrote.
Monaghan and colleagues advised that single-gene tests or gene panel tests are appropriate for first-line use in cases where the structural anomalies are "highly suggestive" of a specific disease, and that exome sequencing should be considered if standard testing workups are not useful.
"At the present time, there are no data supporting the clinical use for [exome sequencing] for other reproductive indications, such as the identification of sonographic markers suggestive of aneuploidy or a history of recurrent unexplained pregnancy loss," they wrote.
The ACMG is also calling for transparency on the part of labs when it comes to methods and limitations of various testing platforms, along with greater communication with ordering clinicians about the technologies used. Ordering clinicians should provide labs with extensive information, including fetal imaging reports, relevant lab reports, and parental medical and family history, the authors advised. For better results, labs should conduct prenatal testing of the fetus as well as screening of the biological parents.
"For laboratories not requiring trio analysis for prenatal [exome sequencing], all efforts should be made to determine inheritance of identified fetal variants with targeted testing of the biological parents," they advised.
Because testing has the potential to reveal incidental findings and variants of uncertain significance, labs need to have "clearly defined policies regarding the types of variants that will be reported for the fetus and parents and under what circumstances," the authors wrote. Labs also need to have an informed consent process to review these policies.
"It is recommended that laboratories offering prenatal [exome sequencing] report pathogenic and likely pathogenic variants, as determined using ACMG variant interpretation guidelines in known disease genes consistent with the reported fetal phenotype," according to Monaghan et al.
For variants of uncertain significance, labs may want to report them when there is a connection with particular conditions under investigation.
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