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ACMG Develops Framework for Use of Fetal Genomic Sequencing

NEW YORK – The American College of Medical Genetics and Genomics (ACMG) has developed new guidelines on the use of exome sequencing in prenatal care.

The new guidelines aim to assist referring physicians, laboratory geneticists, genetic counselors, and other medical professionals in understanding the complexity and implications of using this technology in the prenatal setting, and to guide clinical labs in the development of protocols and policies related to the use of prenatal exome sequencing.

"In May 2012, the ACMG Board approved 'Points to Consider in the Clinical Application of Genomic Sequencing' and, at that time, they did not recommend fetal genomic sequencing," ACMG President Anthony Gregg said in a statement. "New data speaks to ACMG's concerns raised at that time. Among these are turnaround time and guidance on identifying and reporting variants of unknown clinical significance."

In the new document published on Wednesday in the journal Genetics in Medicine, the association addressed pretesting and post-testing considerations, as well as how to report findings in both fetuses and parents, cost considerations, considerations for reanalysis of test results, and education of healthcare professionals.

For example, exome sequencing should only be considered for a fetus with ultrasound anomalies when standard chromosomal microarray analysis and karyotype analysis have failed to yield a definitive diagnosis, the authors suggested. If a specific diagnosis is suspected, molecular testing for the suggested disorder with single-gene test or gene panel should be the initial test. 

"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 added.

Test design — including its genetic content, next-generation sequencing chemistry, and data analysis settings — should also be considered before tests are administered, and clinicians should seek guidance from a lab or medical geneticist regarding the methods and choice of available testing, the researchers said.

In terms of reporting results, the ACMG panel said that while exome sequencing can increase the possibility of making a definitive diagnosis, it can also increase the likelihood of identifying variants of uncertain significance. Therefore, labs should have clearly defined policies regarding the types of variants that will be reported for the fetus and parents and under what circumstances.

The authors also recommended post-test counseling, regardless of the test results, noting that it should be provided by individuals with relevant expertise.

"If a diagnosis is not achieved, prenatal care should be based on the available information from imaging. If a diagnosis is made, the findings may be used to guide further management," the researchers wrote. "It should be emphasized that a negative prenatal exome result does not exclude a genetic diagnosis, and the results should not be used as reassurance of a normal outcome."

Importantly, the researchers added, healthcare professionals should take the time to discuss expectations from genetic testing with each patient before testing is done, taking into account each patient's belief system, and social, religious, and cultural background. Healthcare professionals should be educated regarding the turnaround times, costs, clinical utility, benefits, limitations, and future implications of each kind of test before recommending exome sequencing as an option, the ACMG said.

"Data from prenatal [exome sequencing] may provide new information regarding the spectrum of anomalies in rare disorders or for well-established genetic conditions without known prenatal characteristics," the authors concluded. "It may also contribute to defining the clinical spectrum for lethal disorders, where the full phenotype may not yet be understood. Additional research is needed on patient perspectives of the consent process, effective and appropriate communication of uncertainty, return of results and reinterpretation, and health and economic outcomes."