Ultrasound Obstet Gynecol. 2023 Sep 19. doi: 10.1002/uog.27491. Online ahead of print.
OBJECTIVE: Primarily to determine the incremental yield of Whole Genome Sequencing (WGS) over Chromosome Microarray Assessment (CMA) and/or Exome Sequencing (ES) in fetuses and infants with a congenital anomaly that was or could have been detectable on ultrasound prenatally. Secondly, to evaluate the turnaround time (TAT) and quantity of DNA required for testing using these pathways.
METHODS: OVID MEDLINE(R), EMBASE, Medline (Web of Science), Cochrane Library, and ClinicalTrials.gov databases were searched electronically (January 2010 to December 2022). Inclusion criteria were cohort studies including fetuses/infants with ≥n=3 cases of: (i) one or more congenital anomalies; (ii) an anomaly which was or would have been detectable on prenatal ultrasound and; (iii) exclusion of aneuploidy and pathogenic Copy Number Variants >50kb. Pooled incremental yield was determined using a random-effects model and heterogeneity was assessed statistically using Higgins’ I2 . Sub-analyses were performed based on pre- or postnatal presentation, multi-system anomalies and classification based upon NHS England prenatal (R21) ES inclusion criteria. PROSPERO 2022 CRD42022380483 RESULTS: Eighteen studies incorporating n=1284 cases were included, of which n=8 (44.4%) incorporating n=754 (58.7%) cases were prenatal cohorts and the remainder representing postmortem (postnatal evaluation), neonatal or infants with congenital structural anomalies. The incremental yield of WGS over QF-PCR/CMA was 26% (95% CI 18-36%, I2 =86%), 16% (9-24%, I2 =85%) and 39% (95%CI 27-51%, I2 =53%) for all, prenatal and postnatal cases. The incremental yields were optimal where sequencing was performed in line with NHS England prenatal ES criteria; 32% (22%-42%, I2 =70%). The incremental yield of Variants of Uncertain Significance (VUS) was 18% (95% CI 7-33%, I2 =74%). The yield of WGS over ES was non-significant at 1% (95% CI 0%-4%, I2 =47%). The pooled median TAT for WGS was 18 days (range: 1-912 days) and the quantity of DNA required for WGS versus CMA and ES was 100ng (±0) and 350ng (±50) p=0.03 respectively.
CONCLUSION: Whilst WGS investigation for congenital anomaly holds great promise, for the future, its’ incremental yield over ES is yet to be demonstrated. However, the laboratory pathway for WGS (compared to sequential QF-PCR/CMA/ES) requires less DNA with a potentially faster TAT. There was a relatively high rate of VUS. This article is protected by copyright. All rights reserved.