Use of genome sequencing in the prenatal diagnostic setting is steadily increasing. Karyotyping and chromosomal microarray (CMA) remain the leading strategies for investigating the potential genetic etiology of fetal structural anomalies; however, as more providers recognize the benefits of genome sequencing, its volume is increasing. This growing provider use has prompted position statements for the use of whole exome sequencing (WES) in prenatal cases from professional organizations including the American College of Medical Genetics and Genomics (ACMG), the British Society for Genetic Medicine, and the International Society for Prenatal Diagnosis (ISPD).1-3
Mellis et al. conducted a meta-analysis of literature published between January 2010 and October 2021 to determine the incremental diagnostic yield of WES versus karyotype and CMA. The review included 66 studies representing over 4,000 selected and non-selected probands. The study found that–

Whole exome sequencing provided a diagnosis in an
additional 31% of fetuses with structural anomalies.4

Studies specifically illustrating the utility of prenatal whole genome sequencing (WGS) in the diagnosis of structurally abnormal fetuses are fewer in number yet continue to emerge. One such study prospectively used whole genome sequencing in a cohort of 37 singleton fetuses with ultrasound-identified structural anomalies, resulting in a 19% diagnostic yield.5 A variant of uncertain significance (VUS) with potential clinical significance was identified in an additional 19%. The authors suggest a higher diagnostic yield would have been possible if a multi-sample (parental, trio, etc.) analysis had been performed, providing the ability to identify de novo variants and potentially reclassify the VUSs as pathogenic.

The paper offers support for the use of prenatal whole genome sequencing in this setting and highlights some of the key benefits WGS offers over karyotyping, CMA, and WES, including:

  • Detecting single nucleotide variants (SNVs) and broad range of copy number variants (CNVs) in single, comprehensive test
  • Identifying variants in coding and non-coding regions of the genome
  • Uniform coverage allowing for higher fidelity in detecting CNVs than WES
  • Opportunity for reanalysis of prenatal WGS data to guide pediatric care as the knowledge base of phenotype-gene-disease associations grows
  • Shorter turnaround time for WGS versus serial karyotype/CMA/WES testing strategies

Prenatal Genomic Testing at PerkinElmer Genomics

The case for prenatal genome-wide sequencing in the diagnosis of fetal structural anomalies continues to grow at a rapid pace. As a global leader in genomics, PerkinElmer Genomics offers diagnostic prenatal testing that is sensitive, comprehensive, and fast and includes STAT prenatal whole genome sequencing, whole exome sequencing, CNV testing, and targeted testing to pinpoint familial variants.
With a depth of resources like patient-friendly test guides, an easy-to-use ordering portal, a variety of flexible specimen collection kits, and billing and payment options that offer financial peace of mind, PerkinElmer Genomics is here to assist you with the seamless implementation of prenatal sequencing in your practice.

1 Monaghan KG, et al. The use of fetal exome sequencing in prenatal diagnosis: a points-to-consider document of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2020; 22:675–80.
2 Mone F, et al. Evidence to support the clinical utility of prenatal exome sequencing in evaluation of the fetus with congenital anomalies: Scientific Impact Paper No. 64 [February] 2021; 128(9):e39-e50.
3 Van den Veyver IB, et al. and ISPD Board of Directors. International Society for Prenatal Diagnosis Updated Position Statement on the use of genome-wide sequencing for prenatal diagnosis. Prenat Diagn 2022; 42(6):796-803.
4 Mellis R, et al. Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta-analysis. Prenat Diagn 2022; 42(6):662-85.
5 Wang Y, et al. Diagnostic yield of genome sequencing for prenatal diagnosis of fetal structural anomalies. Prenat Diagn 2022; 42(7):822-30.