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


      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.


      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).


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