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Oral Concurrent Session 9 - Fetal US Genetics

Oral Concurrent Sessions

(86) Genome sequencing as a first-tier prenatal diagnostic test: Is it time to change?

Wednesday, February 14, 2024
3:15 PM – 3:30 PM  
Location: Potomac Ballroom D, Ballroom Level
Objective: Current standard of care (SOC) for routine prenatal testing includes karyotype, FISH, and/or chromosomal microarray (CMA). Exome sequencing is recommended for fetuses with ultrasound anomalies. Evidence demonstrating the utility of genome sequencing (GS) as a single prenatal diagnostic test for structural anomalies and standard indications is limited. We investigated GS as an alternative to SOC testing in a prospective blinded study.

Study Design: 218 fetuses undergoing routine diagnostic SOC testing had GS performed; 132 with ultrasound anomalies and 86 without anomalies. Trio GS testing was performed in 98.6%. Fetuses with aneuploidy detected by FISH were excluded. SOC results were blinded to the laboratory performing GS. SOC reporting criteria followed local clinical laboratory guidelines. Reporting criteria for GS were established by a multidisciplinary team. Reportable variants include clinically significant findings related to the fetal phenotype and/or associated with a severe neonatal, pediatric, or maternal health outcome. Detection rates of reported variants were compared between testing approaches by McNemar analysis.

Results: Overall yield for GS was significantly higher than that of SOC, at 23% compared to 7.3% (p< .0001). In anomalous cases, 31% had reportable findings by GS and 7.6% had reportable findings by SOC (p< .0001). 76% of findings reported by GS and 30% of findings reported by SOC were related to the fetal phenotype. In non-anomalous cases, 10.5% had reportable findings by GS and 7% had reportable findings by SOC (p< .0001). Overall, 4 fetuses had reportable SOC findings missed by GS (2 mosaic tetraploidy, 1 mosaic monosomy X, and 1 balanced translocation) and 47 fetuses had reportable GS findings missed by SOC (single nucleotide variants, indels, copy number variants < 300 kb, uniparental heterodisomy, and repeat expansions).

Conclusion:

GS identifies most disorders detected by SOC testing and reveals additionally relevant genetic findings in the fetus and mother. GS has the potential to become the superior first-tier prenatal diagnostic test, replacing SOC.