Incremental yield of whole‐genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta‐analysis

Abstract

ObjectivePrimarily 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.MethodsOVID 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 CRD42022380483ResultsEighteen 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.ConclusionWhilst 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.

Whole‐genome sequencing analysis in fetal structural anomalies: novel phenotype–genotype discoveries

“…Although the sample size was too small to achieve statistical significance, a limitation of this study, it was sufficient to demonstrate that WGS increased the diagnostic yield over CMA plus ES and has great potential to become a powerful tool for prenatal diagnosis, as supported by previous large studies [12][13][14] .…”

“…During the prenatal period, utilizing WGS is more challenging due to the restricted and non-specific phenotypic information available and the literature assessing the incremental yield of WGS over CMA and/or ES is relatively limited. Hu et al 12 showed that WGS enhanced the detection rate by 5.9% compared with CMA in 185 unselected fetuses with structural anomalies, while a meta-analysis by Shreeve et al 14 demonstrated a 16% incremental yield for WGS over CMA, incorporating 755 prenatal cases from eight studies. When compared to CMA plus ES, Zhou et al 13 demonstrated a comparable yield of 19.8% (n = 110).…”

“…The joint position statement of the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM) and the Perinatal Quality Foundation (PQF) also recommends that WGS be used to diagnose cases with a strong suspicion of genetic disorders and negative CMA findings 11 . Recently, several publications regarding WGS in prenatal diagnosis have shown that it is a powerful tool with some unparalleled advantages, such as enhancing an additional diagnostic rate of 5.9% in cases compared with CMA 12 , as well as a relatively short turnaround time and less DNA consumption 13,14 . However, data on integrating WGS into prenatal clinical practice remain limited.…”

Whole‐genome sequencing in prenatally detected congenital malformations: prospective cohort study in clinical setting

“…It is apparent that MPS, whether it be WGS or ES, is beneficial in prenatal diagnosis. However, a recent systematic review, concluded that the incremental yield of WGS over CMA and ES is small and statistically non‐significant in the investigation of congenital malformations detected in the perinatal period or during infancy 27 . On the other hand, another recent study of 17 fetuses with aberrations detected by ultrasound showed an incremental diagnostic yield of 11.8% in WGS over CMA and ES, as WGS detected two small‐size exon‐level CNVs beyond the detection levels of CMA and ES 28 .…”

High‐throughput sequencing in prenatal care: how to combine diagnostic performance and best practice?

“…We believe that the prescription of extended genetic analyses, such as WES or WGS, should be offered as part of a strategy aimed at possibly influencing the course of pregnancy 3 . If this is not the case, it makes sense to perform these analyses in the postnatal (or postmortem) period, when phenotypic characterization is most relevant, to enable optimal interpretation of high‐throughput sequencing data by reverse phenotyping if needed 4 .…”