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Use of fetal genetic sequencing increases the detection rate of genetic findings

January 23, 2017

In a study to be presented Thursday, Jan. 26, in the oral plenary session at 8 a.m. PST, at the Society for Maternal-Fetal Medicine's annual meeting, The Pregnancy Meeting™, researchers with the Columbia University Medical Center in New York found that, in preliminary data, fetal genomic (whole exome) sequencing (WES) as a diagnostic test for women with pregnancies complicated by major fetal congenital anomalies increased the detection rate of genetic findings by between 10 to 30 percent.

The study, titled Whole exome sequencing in the evaluation of fetal structural anomalies: A prospective study of sequential patients used selected patients that were felt to have a high likelihood of having a fetal genetic anomaly.

In recent years, prenatal detection of fetal congenital anomalies has become increasingly more frequent, due to the adoption of routine ultrasound imaging. Simultaneously, advanced genetic testing has evolved demonstrating that an increasing proportion of these anomalies have a genetic cause. Approximately 10 years ago, chromosomal microarray analysis (CMA) was added to standard karyotyping as a prenatal diagnostic test increasing the detection rate of clinically significant cytogenetic abnormalities by 6% in cases with a single anomaly (abnormality) and 13% when multiple anomalies were present. In other words, CMA looked at cell and chromosomal disorders. These prior studies, including a multi-center Eunice Kennedy Shriver National Institutes Child Health and Human Development (NICHD)-funded trial presented at a prior Society of Maternal-Fetal Medicine annual meeting, has changed national guidelines so that CMA is now the recommended test for evaluating fetal anomalies.

While CMA has been a significant improvement, an estimated 60-70% of cases with identified fetal abnormalities still remain without a genetic diagnosis. With this current study, fetal genomic (whole exome) sequencing was evaluated as a diagnostic test for women with pregnancies complicated by major fetal congenital anomalies.

"Our preliminary data and published literature indicate that sequencing will increase the detection rate of genetic findings and this information will significantly improve patient counseling and neonatal treatment," explained Ronald Wapner, M.D., professor of obstetrics and gynecology for the maternal fetal medicine department at Columbia University Medical Center, who is presenting the study. "New associations with genes with very specific fetal phenotypes are also beginning to be uncovered," he added.
A copy of the abstract is available at and below. For interviews please contact Vicki Bendure at 202-374-9259 (cell).

About the Society for Maternal-Fetal Medicine

The Society for Maternal-Fetal Medicine (est. 1977) is the premiere membership organization for obstetricians/gynecologists who have additional formal education and training in maternal-fetal medicine. The society is devoted to reducing high-risk pregnancy complications by sharing expertise through continuing education to its 2,000 members on the latest pregnancy assessment and treatment methods. It also serves as an advocate for improving public policy, and expanding research funding and opportunities for maternal-fetal medicine. The group hosts an annual meeting in which groundbreaking new ideas and research in the area of maternal-fetal medicine are shared and discussed. For more information visit

Abstract #8 Whole exome sequencing in the evaluation of fetal structural anomalies: A prospective study of sequential patients

Ronald Wapner, Slav Petrovski, Kelly Brennan, Louise Bier, Karen Wou, David Goldstein Columbia University Medical Center, New York, NY

Objective: Small studies have reported the use of whole exome sequencing (WES) in the prenatal evaluation of fetal structural anomalies and have reported pathogenic variant rates of 10-30%. These studies however have all used selected patients that were felt to have a high likelihood of having a genetic etiology. We sought to evaluate the incremental value of WES in routine prenatal diagnosis including all structural anomalies.

Study Design: Under an IRB protocol, all sequential patients with a fetal structural anomaly were offered WES as part of the fetal genetic evaluation. Those having diagnostic prenatal testing had WES, karyotype, and chromosomal microarray done on amniotic fluid or CVS and those not having PND had cord blood obtained at birth for testing. All results were returned to the patients.

Results: Of 127 completed cases, 7 (5.5%) had an abnormal array or karyotype. Of the remaining 120, 9 (7.5%) had a causal pathogenic variant identified (Table 1) and 31.7% had a "plausible" but unproven variant. Of the 35 with multiple anomalies 5 (14.3%) had a pathogenic variant. CNS (18.5%) and GU (16.7%) anomalies had the highest frequency of pathogenic variants (Table 2). Of those with an NT ? 3.5mm or a cystic hygroma only 3.6% had a pathogenic variant. Overall, we found that individuals ascertained through this study were more likely to carry a deleterious-predicted putative de novo mutation affecting an intolerant OMIM disease-associated gene than 1,911 control trios seen in our center (12.5% vs. 3.0%; p=1x10-5). They were also significantly more likely to carry a putative loss-of-function (LoF) de novo mutation in a gene described as LoF depleted (7.5% vs. 1.7%; p=4.6x10-4).

Conclusion: In the evaluation of unselected fetal anomalies, WES adds additional clinically relevant information.

Society for Maternal-Fetal Medicine

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