Abstract
BackgroundExome sequencing is now being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. One reason for this is the paucity of information about the clinical utility of exome sequencing in the prenatal setting.MethodsWe retrospectively reviewed indications, results, time to results (turnaround time, TAT), and impact of exome results for 146 consecutive “fetal exomes” performed in a clinical diagnostic laboratory between March 2012 and November 2017. We define a fetal exome as one performed on a sample obtained from a fetus or a product of conception with at least one structural anomaly detected by prenatal imaging or autopsy. Statistical comparisons were performed using Fisher’s exact test.ResultsPrenatal exome yielded an overall molecular diagnostic rate of 32% (n = 46/146). Of the 46 molecular diagnoses, 50% were autosomal dominant disorders (n = 23/46), 41% were autosomal recessive disorders (n = 19/46), and 9% were X-linked disorders (n = 4/46). The molecular diagnostic rate was highest for fetuses with anomalies affecting multiple organ systems and for fetuses with craniofacial anomalies. Out of 146 cases, a prenatal trio exome option designed for ongoing pregnancies was performed on 62 fetal specimens, resulting in a diagnostic yield of 35% with an average TAT of 14 days for initial reporting (excluding tissue culture time). The molecular diagnoses led to refined recurrence risk estimates, altered medical management, and informed reproductive planning for families.ConclusionExome sequencing is a useful diagnostic tool when fetal structural anomalies suggest a genetic etiology, but other standard prenatal genetic tests did not provide a diagnosis.
Highlights
Exome sequencing is being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited
We defined the following inclusion criteria: (1) the fetal sample was obtained through an invasive diagnostic procedure or product of conception (POC), (2) the fetus had at least one structural anomaly detected by fetal imaging or autopsy, (3) exome sequencing (ES) was performed at Baylor Genetics, and (4) a final report was issued between March 2012 and November 2017
If a fetus had multiple abnormalities within the same top-branch category, that category was only counted once for that fetus. This analysis revealed that the molecular diagnostic rate in fetuses with abnormalities affecting multiple organ systems is higher compared to fetuses with abnormalities in a single organ system (p = 0.018, Fig. 1a and Additional file 1: Table S5)
Summary
Exome sequencing is being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. Congenital fetal anomalies occur in approximately 3% of pregnancies and are responsible for 20% of infant mortality in the USA [1, 2] Many of these are thought to have an underlying genetic etiology. While these genetic testing approaches are invaluable for prenatal genetic diagnosis, the potential etiology for fetal anomalies remains unsolved in approximately 60% of cases. Clinicians relied on serial sequencing of single genes or gene panels to explore a potential molecular diagnosis for a Mendelian disease trait. Such approaches usually require a fairly narrow differential diagnosis and are time consuming. Even when the clinical phenotype manifested during pregnancy is highly specific, targeted gene tests may yield negative results if the disorder is caused by a variant in a disease gene that is not included in the chosen panel
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