Prenatal exome and genome sequencing for fetal structural abnormalities

Access to prenatal exome sequencing for fetal malformations: A qualitative landscape analysis in the US

“…And especially imagining a genetic counselor in Mississippi, for example, where there's one or two prenatal counselors and she sees like 30 patients a week, and she's dealing with the political, everything that's happening there right now. Does she also need to be contacting the 10 -1399 completed in that moment… because I was so worried about them disappearing forever.…”

“…A study on US private payers' perspectives on insurance coverage found that while payers saw value in ES for pediatric patients, they did not see merit in its use for prenatal testing. 2 However, studies have demonstrated a high diagnostic yield of ES for fetal structural anomalies [3][4][5][6][7][8][9] with diagnostic rates ranging from 8.5% to 44% 10 depending in part on phenotypic sub-groups. 11 Given this high yield, several professional societies now recommend the consideration of ES in cases with multiple fetal structural anomalies or in which a genetic disease is strongly suspected.…”

Enhancement of phenotyping for fetal investigation using next‐generation sequencing

“…Next-generation sequencing (NGS), particularly exome sequencing (ES), is being utilized increasingly worldwide to investigate the fetus with structural anomalies, in an attempt to identify potential monogenic disease 4,5 . The use of ES allows a relatively conservative evaluation (including 1-2% of the total genome, but at least 85% of known pathogenic variants) of developmental genetic disease 6 , maximizing the diagnostic yield of pathogenic variants whilst minimizing the identification of variants of unknown significance 4 . There is ongoing debate as to whether whole-genome sequencing (WGS) could further increase the diagnostic yield of pathogenic variants (by interrogating not only the exome, but also intronic regions, splice sites, and the mitochondrial genome and intergenic sequences), as well as simplifying the laboratory process and reducing the turnaround time of results 4,5 .…”

“…The use of ES allows a relatively conservative evaluation (including 1-2% of the total genome, but at least 85% of known pathogenic variants) of developmental genetic disease 6 , maximizing the diagnostic yield of pathogenic variants whilst minimizing the identification of variants of unknown significance 4 . There is ongoing debate as to whether whole-genome sequencing (WGS) could further increase the diagnostic yield of pathogenic variants (by interrogating not only the exome, but also intronic regions, splice sites, and the mitochondrial genome and intergenic sequences), as well as simplifying the laboratory process and reducing the turnaround time of results 4,5 . However, the biggest challenge in applying this technology to prenatal diagnosis is the selection of fetal cases by identification of high-risk phenotypes.…”

“…When fetal abnormalities are identified, further prospective evaluation frequently includes invasive prenatal testing to detect aneuploidy or pathogenic copy number variants, which are present in up to 25% of cases 3 . Next-generation sequencing (NGS), particularly exome sequencing (ES), is being utilized increasingly worldwide to investigate the fetus with structural anomalies, in an attempt to identify potential monogenic disease 4,5 . The use of ES allows a relatively conservative evaluation (including 1-2% of the total genome, but at least 85% of known pathogenic variants) of developmental genetic disease 6 , maximizing the diagnostic yield of pathogenic variants whilst minimizing the identification of variants of unknown significance 4 .…”