Secondary and incidental findings
In clinical practice, variants of uncertain significance (VUS) are those where pathogenicity is unclear. If fed back to patients they may cause significant anxiety and make patient decision making more complex (especially in the context of a fetal structural abnormality identified in a pregnancy were termination of pregnancy is an option). Parents report that such information is ‘toxic’ and emotional effects may last for a considerable period41,42,43.Therefore, as prenatal ES is used to evaluate congenital malformations in clinical practice there is a need to register VUS and the fetal phenotype in an international registry with comprehensive clinical access.
Secondary findings are genetic variants, unrelated to the primary presentation (of the probands) but may be reported if deemed “medically actionable”9. In a paediatric setting, the American College of Medical Genetics and Genomic (ACMG) has set out guidelines that state when offering ES, secondary findings should be reported in 59 genes (in which it is believed that there is clinical evidence that pathologic variants may result in disease that may be prevented or treated)44. However, in this guidance, there is an exclusion of prenatal ES. The extension of this process to prenatal diagnosis (and the parental samples of trios) has been debated and is controversial45. An example of this would be the potential ES testing of a fetus with a phenotype suggestive of Fanconi anaemia46. Somatic inactivation of the Fanconi anaemia /BRCA pathway accounts for the chromosomal instability the predisposition of some cancers (breast, bowel, and ovary) in the general population47. However, it is recommended that if instituted it should be presently on a case by case basis and pre-and post-test counselling of parents is careful and detailed before this is instituted. In addition, trio ES could also reveal unforeseen issues such as non-paternity or parental consanguinity again leading to difficult counselling scenarios48,49.
Pre-test and post-test counselling .
A more than superficial understanding of prenatal ES by parents and its implications for the pregnancy, themselves, their family and future pregnancies is extremely important and cannot be overstated. In the UK, prenatal test counselling in pregnancy has been traditionally the role of screening midwives and when prenatal invasive tests are contemplated it is the obstetrician who usually discusses the procedure and laboratory test to the parents. In North America, this role is often taken up by the genetics team, commonly the specialist genetics nurse. The pre-test counselling for potential prenatal ES, therefore, needs to be detailed and intelligible. It must be emphasised that such testing is new and the clinical utility, sensitivity and specificity of diagnosis (depending upon the fetal phenotype) are emerging from research studies and will undergo further review as these tests are utilised in clinical practice. There is broad agreement that this should be led by genetic healthcare professionals. However, the challenges of delivering such information to parents (at an emotive time in their pregnancy when a fetal abnormality has been detected) with varying educational, religious and cultural backgrounds and experiences should not be understated9. Our own experience, piloting prenatal ES, is to have a multidisciplinary meeting (to discuss the case study and imaging) and to be conservative about fetal phenotype selectionprior to offering the testing 50. If the multidisciplinary team (comprising the same group of specialists as used in the PAGE study)27 decide that the pregnant women may be offered such testing, the couple are seen in a multidisciplinary combined fetal medicine/genetic clinic where a repeat ultrasound examination is performed (and previous information from the family pedigree, diagnostic imaging and tests reviewed). The couple then have pre-test counselling by a fetal medicine subspecialist and a clinical geneticist9,50.
Once the laboratory based ES and potential variants have undergone bio-informative filtering, then a multidisciplinary clinical review panel is essential to discuss the clinical significance of any variant identification and to elucidate the potential likelihood of causation in the associated fetal abnormality(ies). Once a causative genetic variant has been identified, this again, needs to be discussed with the parents within a multidisciplinary clinic with the clinical genetic team explaining clinical relevance, potential inheritance and any further testing (especially of family members). Such complex clinical pathways and infrastructure are starting to be developed in the UK and multidisciplinary research (through the Optimising EX omePRE natal S equencing S ervices [EXPRESS study]) is underway to aid the development of such pathways and to ensure equity of access and high clinical standards across England51.