4: Have genomic screening advances gone far enough?


      Advances in genomics have expanded the screening modalities available in pregnancy. Expanded carrier screening (ECS) is used to identify couples with reproductive risks for autosomal recessive (AR) and X-linked (XLR) disorders, and cell-free fetal DNA prenatal multigene screening (cffMGS) is available to detect de novo single base pair mutations noninvasively. We sought to determine the ability of ECS and cffMGS individually and in combination to detect genetic syndromes identified in a cohort of fetuses with congenital anomalies.

      Study Design

      Since 2015 we have offered whole exome sequencing (WES) to all parents with a fetus possessing any structural anomaly. Fetuses with a proven single gene variant causing the anomaly formed the basis of the present study. We evaluated whether the genomic finding would have been identified by one of 7 commercially available ECS panels and/or 1 commercially available cffMGS panel. ECS panels used targeted sequencing for detection of carriers and included between 141 and 992 genes. The cffMGS panel included 30 genes.


      364 fetuses with ultrasound-identified anomalies, a normal karyotype and a nonpathogenic microarray had WES via trio analysis. Among these, there were 14 (3.8%) AR, 3 (0.8%) inherited XLR, and 27 (7.4%) de novo diagnoses. Parental sequencing confirmed the mothers of the XLR cases were carriers, as were both parents of the AR disorders (Table 1). Trio analysis confirmed de novo findings in all de novo dominant cases (Table 2). Detection by ECS panel of the causative AR and XLR genes ranged from 0 to 11, with larger panels identifying a greater number of causative genes. Two ECS panels would miss all 17 at-risk couples. The largest ECS panel included 73% of the pathogenic genes identified in our cohort. Among the 27 de novo variants, cffMGS could potentially have detected 8/27 (29.6%). The combined use of the largest ECS panel and cffMGS could have detected up to 43.2% of causative genes in the present study cohort. Commonly used ECS panels (<400 genes) in combination with cffMGS could have detected 22.3% of causative mutations in the present study cohort.


      Increasing the number of genes included on ECS and cffMGS screening panels has the potential to enhance early detection of fetal anomalies caused by Mendelian disease.
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