New work led by researchers from China has shown that whole-genome sequencing could offer a better approach for prenatal testing with improved detection capability.
Anomalies of the central nervous system (CNS) rank among the most widespread congenital abnormalities. Cases of just neural tube defects (NTDs) are put at 18.6 per 10,000.
Prenatal testing is a form of prenatal care that aims at detecting anatomic and/or physiologic problems affecting a baby in the womb as early as possible. Couples who are intentional about having healthy babies depend on prenatal tests for guidance on what to do during pregnancy.
This new research carried out in a large cohort by BGI Genomics scientists in partnership with counterparts from the Maternal and Child Health Hospital of Hubei Province for the time unraveled the genomic architecture of fetal CNS anomalies. It showed how the detection of these defects may be improved with whole-genome sequencing.
There are several methods aimed at uncovering issues with the fetus before it is given birth to. These differ in terms of effectiveness, use, and invasiveness.
Ultrasonography is a more popular option out of the available testing methods. It is regarded highly for its ability to detect CNS defects. The non-invasive nature of this technique also contributes to it being preferred more than some other alternatives.
It is very thorny to diagnose fetal CNS defects using imaging methods, as per researchers. The challenge has to do with the ongoing development of the fetus along with its brain.
Quality research on the traits that CNS-related genetic conditions present in imaging tests is lacking. This is despite the numerous studies on such conditions that scientists have already carried out.
There was also a lack of genomics studies on fetal CNS anomalies that involved large cohorts. This makes the new work, which appeared in npj Genomic Medicine, notable.
Improved defect detection
The research team adopted a two-step approach for its analysis.
First, the researchers used low-depth whole-genome sequencing for their analysis of aneuploidy and copy number variants (CNVs).
Aneuploidy is a type of genetic disorder that is characterized by an irregular number of chromosomes. For example, there could be an extra chromosome or a missing one instead of the normal 46. An irregular chromosome number could have an effect on pregnancy outcomes.
In the second step, the team applied 40-fold (40X) whole-genome sequencing to negative samples from the low-depth sequencing for further analysis of single nucleotide variants (SNVs) and small fragment copy number variants. It wanted to work out genes linked to fetal CNS anomalies and highlight the potential of whole-genome sequencing as a tool for clinical diagnosis.
The researchers gathered 162 CNS anomaly-related clinical samples between 2015 and 2017. They identified 18 aneuploidy variants, 21 CNVs, three small fragment CNVs, and 26 SNVs that were deemed pathogenic or had the potential of becoming so. The SNVs included 15 novel mutations.
The team reported a 38.3 percent detection rate through statistical analysis of the variants, with 62 cases of CNS defects successfully diagnosed. Also, the detection rate for microcephaly and total forebrain abnormalities exceeded 70 percent.
A better test
According to the researchers in this study, whole-genome sequencing proved to be more comprehensive than others tests in clinical use currently.
Five of the 29 major genes having diagnostic variants and detected by the researchers were found in more than a sample. They were spotted in about 71 percent of fetuses having both CNS and non-CNS defects. By contrast, researchers found them in 24.6 percent of fetuses that had only CNS anomalies.
The detection rates of low-depth whole-genome sequencing assays for microscopic CNVs were comparable to those of karyotyping. It also uncovered an extra 2.3 percent of submicroscopic pathogenic CNVs in samples that had no microscopic CNVs.
Researchers found that the anomaly detection rate of 40-fold whole-genome sequencing was about 19 percent higher, compared to the low-depth alternative. They said its detection rate, on the whole, trumps the rate of whole-exome sequencing.
Whole-genome sequencing was also found to be better in terms of costs and the time it takes to do. The sequencing costs are lower compared to combined chromosome microarray and exome sequencing. Analysis time is also reduced to a level comparable to the time for exome sequencing and shorter than the time for combined chromosome microarray analysis and exome sequencing.
However, it is currently difficult to establish the real clinical significance of certain detected variants as a result of database constraints.
The use of whole-genome sequencing for prenatal testing can get better at some point after researchers have analyzed more samples. Also, scientists can extend the analysis to each of the anatomical systems.