Abstract
ObjectiveThe purpose of this study was to explore the diagnostic yield and clinical utility of trio‐based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging.MethodsIn this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7).ResultsA conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases.ConclusionsThese results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making.
Highlights
Fetal congenital anomalies are detected in 2% to 5% of pregnancies by routine ultrasound.[1,2] The occurrence of these anomalies can cause significant distress for the expecting parents and have a major impact on perinatal mortality and long-term morbidity.[3,4] The underlying etiology of these anomalies is diverse and includes genetic factors
Since January 2016, rapid whole exome sequencing (rWES) has been offered as a routine diagnostic test at the Radboudumc for cases whose medical management could be directly impacted by a genetic diagnosis
A pathogenic copy number variations (CNVs) was detected in two of the 47 cases for whom chromosomal microarray analysis (CMA) was performed prior to, or in parallel with, rWES: in case #51 a de novo pathogenic deletion of 17p13.3 (Miller-Dieker Lissencephaly syndrome, OMIM #247200) was detected in the medical center of referral (Appendix S1). This copy number variant, retrospectively identified in rWES, was initially not reported by rWES, as analysis was restricted to the gene panel requested which did not include the genomic loci of the genes in the 17p13.3 region
Summary
Fetal congenital anomalies are detected in 2% to 5% of pregnancies by routine ultrasound.[1,2] The occurrence of these anomalies can cause significant distress for the expecting parents and have a major impact on perinatal mortality and long-term morbidity.[3,4] The underlying etiology of these anomalies is diverse and includes genetic factors. Current routine prenatal genetic testing strategies often include molecular rapid aneuploidy testing (RAD) and chromosomal microarray analysis (CMA), designed to detect numerical and structural chromosome abnormalities, respectively, which show a combined diagnostic yield of approximately 40%.5,6 This means that for the large majority of cases, the underlying cause of the identified congenital anomalies remains unknown. In a recent study on the use of rWES for fetuses presenting with skeletal anomalies, 81% of cases were genetically diagnosed.[14] this increase in diagnoses enabled more accurate prediction of pregnancy outcome, providing parents more certainty in prenatal decision making, the contribution of skeletal anomalies only accounts for around 30% of all fetal congenital anomalies.[15,16] The efficacy of adopting rWES as a first tier test for the full spectrum of fetal congenital anomalies detected during routine ultrasound imaging has been recently studied in a few pilot studies.[17,18,19,20] The vast majority of these studies focused on the diagnostic yield and TAT as outcome parameters, rather than focusing the effect of the rWES result on clinical decision making. Rapid aggregation of prenatal molecular and clinical information into a conclusive diagnosis is challenging and requires cooperation of a dedicated team
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