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.