Diagnostic yield of genome sequencing for prenatal diagnosis of fetal structural anomalies

Abstract

Objective: Genome sequencing (GS >30x) is beginning to be adopted as a comprehensive genome-wide test for the diagnosis of rare disease in the post-natal setting. Recent studies demonstrated the utility of exome sequencing (ES) in prenatal diagnosis, we investigate the potential benefits for GS to act as a comprehensive prenatal test for diagnosis of fetal abnormalities. Methods:We performed GS on a prospective cohort of 37 singleton fetuses with ultrasound-identified structural abnormalities undergoing invasive prenatal testing.GS was performed in parallel with standard diagnostic testing, and the prioritized variants were classified according to ACMG guidelines and reviewed by a panel of board-certified laboratory and clinical geneticists.Results: Diagnostic sequence variants were identified in 5 fetuses (14%), with pathogenic variants found in NIPBL, FOXF1, RERE, AMMECR1, and FLT4. A further 7 fetuses (19%) had variants of uncertain significance (VUS) that may explain the phenotypes. Importantly, GS also identified all pathogenic variants reported by clinical microarray (2 CNVs, 5%). Conclusion:Prenatal GS offered diagnoses (sequence variants and CNVs) in 19% of fetuses with structural anomalies. GS has the potential of replacing multiple consecutive tests, including microarray, gene panels, and WES, to provide the most comprehensive analysis in a timely manner necessary for prenatal diagnosis. Key pointsWhat's already known about this topic? � Current prenatal diagnostic protocol in Canada includes rapid aneuploidy detection (RAD) followed by microarray analysis.� The diagnostic yield of Exome sequencing in fetuses with ultrasound abnormalities and negative results by RAD and CMA is 8.5%-10%. However, the clinical utility of genome sequencing in prenatal settings is not established.

International Society for Prenatal Diagnosis Updated Position Statement on the use of genome‐wide sequencing for prenatal diagnosis

“…Some include sequencing and interpretation of variants in the exons of nearly all genes, while others focus on the “clinical exome”, a collection of 4000–5000 genes causatively associated with known single gene disorders catalogued in OMIM, or alternatively, on the ∼1600 genes clearly associated with genetic conditions known to present with malformations detectable in the fetus or neonate 3 . Furthermore, small series of prenatal genome sequencing (pGS) are now emerging 9 and there are ongoing trials evaluating pGS. The use of pES and pGS is likely to increase as interpretive tools and appropriate data sources continue to be improved, and costs continue to fall.…”

Next Generation Sequencing after Invasive Prenatal Testing in Fetuses with Congenital Malformations: Prenatal or Neonatal Investigation

“…There is clear evidence to support the use of exome sequencing in multi-system congenital abnormalities, however does it offer additional yield in single system disease? The evidence from the cohorts that have followed the PAGE Study and Petrovski et al demonstrate significant incremental diagnostic yield of exome sequencing as a secondary diagnostic genetic test for single system congenital abnormalities, with particular focus on cardiac and neurological anomalies, increased nuchal translucency and non-immune fetal hydrops [ 29 , 32 , 33 , 36 ]. This supports its translation into routine clinical practice in Fetal Medicine departments for the diagnosis of monogenic conditions in fetuses with both multi- and single system abnormalities.…”

“…As the cost and turnaround time of WGS decreases, with technological and bioinformatic pathway advances, and our understanding of the non-coding region of the genome improves, it has the potential to supersede ES for enhanced diagnostic genetic testing in cases of fetal malformations. Although pES is the predominant approach for prenatal genetic testing, small series of prenatal whole genome sequencing are now emerging and there are ongoing trials [ 32 ]. The use of genome-wide sequencing was recently covered by an updated position statement by the International Society for Prenatal Diagnosis (ISPD) [ 33 ].…”

Prenatal exomes and genomes – so much new and so much more to learn

“…10 Such information changes counseling, since standard testing with CMA has lower yield for these diagnoses and also highlights the importance of collaboration and combining data from multiple cohorts. Other series from around the world are included in the second special issue to be published in June, and report sequencing yield for a variety indications of including hydrops, cardiac defects and renal anomalies, [11][12][13][14][15][16] again showing significant incremental diagnostic yields. Another interesting report on Non-Immune Hydrops Fetalis (NIHF) by Reytan and colleagues describes a fetus with NIHF with compound heterozygous deletions of PIEZO1.…”

“…Among the series we report, two are specifically exploring pGS as opposed to pES. 12,13 pGS has the potential to more easily ascertain balanced and unbalanced chromosomal rearrangements and CNVs.…”