Prenatal diagnosis: New study suggests exome sequencing could replace microarray as a first-tier test for severe central nervous system anomalies

Microarray vs NGS

Prenatal genetic testing is regularly performed in high-risk pregnancies to identify or confirm fetal abnormalities, and molecular cytogenetic methods have constituted the recommended practice for prenatal testing for several decades. Karyotyping first enabled the diagnosis of large-scale chromosomal abnormalities. Then, in the early 21st century, chromosomal microarray analysis (CMA, or just microarray) enabled the identification of submicroscopic copy number variants (CNVs), significantly increasing the prenatal diagnostic yield and consequently becoming the benchmark first-tier genetic test for fetal structural anomalies.

Prenatal diagnosis

Accurate genetic diagnostic solutions are of significant importance in the prenatal stage, mainly given the challenging identification of phenotypes. Fetal physical assessment is limited to imaging techniques such as ultrasound, or fetal MRI at best. It has also been thoroughly reported that, even in the presence of pathogenic variants, prenatal cases may have variable expression and incomplete penetrance, which makes them harder to match to the phenotypic information available on most databases. Other issues that are very important to consider are the time constraints present in pregnancy, and the psychological impact that inconclusive results can have on the expectant families.

The novelty of the study

To shed some light on the debate as to which should be the standard genetic test for prenatal cases involving the CNS, the journal Ultrasound in Obstetrics & Gynecology recently published an article that compared the diagnostic yield between CMA and pES in fetuses with major central nervous system (CNS) anomalies. The study aims to establish which type of testing has the highest diagnostic yield for fetuses with major CNS malformations. Establishing which is the best prenatal diagnosis tool is of special relevance taking into account the time-sensitive context of pregnancy, and the fact that the recurrence rate can have a great impact on future family planning choices.

Bioinformatic details

All cases were analyzed using hg19 as a reference genome. CMA analysis was performed with ChAS Software by Affymetrix, and pES cases were processed using the Franklin genetic analysis platform, end-to-end, from FASTQ to report. All variants were classified according to the latest American College of Medical Genetics and Genomics (ACMG) guidelines as Pathogenic, Likely Pathogenic, Variant of Uncertain Significance (VUS), Likely Benign, or Benign.

The verdict

The study reports that in 38 out of the 86 CMA-negative cases that agreed to further testing, pathogenic or likely pathogenic variants were uncovered by pES analysis. Using NGS after normal microarray results on cases with major CNS malformations resulted in a 44% added diagnostic yield, on top of the 10% provided by CMA testing. Interestingly, the researchers found that this percentage was even higher for specific CNS disorders, such as cases with multiple brain anomalies, reaching an impressive 58% added diagnostic yield.

The future of prenatal testing

The question of prenatal diagnosis doesn’t end here. The role of next-generation sequencing in fetal genotyping is open for debate, and experts are still divided on which of the currently available technologies will be the golden standard for testing in the future.

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Franklin by Genoox

Franklin by Genoox

The world’s largest, most diverse real-world genetic evidence database. We believe that community data-sharing is the future of genomics