DNA sequencing is the process of finding the order of the building blocks (i.e. nucleotides) of the genetic code of an individual.
Whole genome sequencing (WGS) is a next-generation sequencing (NGS) method that is increasingly being used, and it involves sequencing both the non-protein coding (introns) and protein coding (exon) regions in an individual. It is currently the most comprehensive genetic test available and would obviate the need to do WES and CMA.
Reasons for doing prenatal WGS
Prenatal WGS can be performed on fetal cells obtained from amniocentesis or placental cells obtained from chorionic villus sampling when:
1. there are multiple and many isolated fetal structural abnormalities detected by detailed ultrasound scans.
2. there are certain isolated fetal structural abnormalities or certain ultrasound markers (e.g. increased nuchal translucency >= 4.5 mm)
3. past history of pregnancies where the fetus(es) was / were affected with genetic syndromes
WGS is a more comprehensive test and hence more expensive test than WES. More and more researchers are now finding that mutations outside the exome may also cause diseases. WES and CMA may miss such mutations. However, the current ability to interpret the intronic regions is relatively limited still. It is better than WES at detecting copy number variants, trinucleotide repeat disorders, chromosomal rearrangements and mitochondrial disorders. It has a faster turn around time than WES. In future, when the cost of WGS reduces, it will probably replace both CMA and WES.
Limitations of prenatal WGS
1. The main limitation of WGS is that it is more expensive than WES. This limits its use in clinical practice.
2. Another limitation is that a vast amount of data is generated which requires extensive analysis and interpretation which is difficult as a large number of genetic variants have not been identified as benign or pathogenic. This could result in errors of interpretation.
Very often, a proper interpretation can only take place after a consultation with an expert fetal medicine specialist to interpret the scan findings, a laboratory to explore the available libraries for the different mutations detected, and a clinical geneticist to interpret the likelihood that the mutations can cause a disease and the possible range of diseases that the mutations can cause. Our clinic provides the expert fetal medicine assessment, counselling and procedures like amniocentesis / chorionic villus sampling, and we tie up with top genetic laboratories around the world and we refer you to local clinical geneticists for pre- and post-test counselling.
3. Even WGS does not detect all genetic diseases. Some genetic diseases like mosaicism may not be detected by WGS.
4. WGS cannot detect multifactorial diseases (that are affected by both genetic and non-genetic factors) and diseases not affected by non-genetic factors.
WGS (trio) or WGS (single)?
For the fetus, it is recommended that the fetus and both parents be analysed with WGS (trio) as speed is of the essence for analysis during the pregnancy. If the fetus has a VOUS detected and one of the parents carries similar VOUS mutations and do not manifest any disease, then it is more reassuring. If the fetus has a VOUS detected and none of the parents carries similar VOUS mutations, then it is a de novo mutation and could be more worrying in terms of the predicted outcome. Doing a WGS (single) on the fetus only and then doing the parents' WGS only if VOUS is detected may be a cheaper strategy but the proper interpretation of the results would be delayed as then the geneticist could be waiting a further few weeks for the parental WGS results.
Potential unintended consequences of performing prenatal WGS:
It may reveal information about family relationships e.g. that the husband of the mother may not be the biological father of the child, or that the couple may be related by blood.
It may reveal that a parent of the affected fetus is also affected by the same genetic condition, which may have medical consequences for the parent (even if he/she is currently asymptomatic) and his/her family members. This may have negative implications on the insurability of the parent with the genetic condition.
It may reveal unexpected / incidental medical information (known as secondary findings) about the child or the parents. Such secondary findings are not related to the reason for doing the test. The American College of Medical Genetics and Genomics has recommended that consideration be given for mutations in 57 specific genes (e.g. inherited cancer syndromes, connective tissue disorders associated with sudden cardiac events, certain types of heart disease, high cholesterol, rare genetic susceptibility to complications from anaesthesia when certain drugs are used) generally unrelated to the presenting problem to be reported as these may benefit you to know as there could be certain interventions that could reduce the complications of the genetic condition in the affected individuals. Knowing about these secondary findings could also cause anxiety / stress to the family and possibly affect the insurability of the individuals adversely. Knowledge of certain secondary findings may lead to more medical screening, procedures and testing for your child, you and possibly other family members. One may choose not to receive secondary findings specifically in your child's report or your report. You could also choose to receive the child's report only after the child has been delivered. If you had chosen not to receive report about any secondary findings, this information would then not be available to you or your health insurance company.
The results may be classified as:
2) likely pathogenic
3) variation of unknown significance
4) likely benign
The report would include:
Primary result where genetic changes that are likely related to your child's condition will be discussed in detail
Secondary findings (see above). In addition to ACMG's 57 medically actionable genes, different laboratories may also report different sets of other secondary findings.