Prenatal carrier screening & prenatal exome sequencing

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from Luke’s Journal 2018 | Hot Topics #1 | Vol. 23 No. 3

Death is considered a failure and an end of biological life as we know it.

Depending on our worldviews, we have different mechanisms of coping with death – especially the death of a baby. Faith and hope of seeing the baby again; despair and depression; and anger and frustration at the lack of available medical technology are all legitimate expressions of grief. When loss is repeated in a subsequent pregnancy, there is a further increase in grief and doubts about one’s intrinsic capacity to ever have a child. Peri-natal genetic testing adds further complexity to this already emotional time.

In a recent case at the Maternal Foetal Medicine centre where I work, I managed a pregnancy from early stages of foetal formation. The couple and I felt a milestone had passed when the morphology scan at twenty weeks was within normal limits. The previous pregnancy had ended with the baby dying soon after birth in spite of several foetal interventions and an anxious forty weeks. On subsequent scans, hope slowly turned to despair as this foetus began to display the same features as the previous baby that had died. The family in desperation asked, “What now”?

The pursuit for answers is not only a clinical imperative but also a compassionate response to a challenging situation (Pisnoli 2016). This is not an uncommon occurrence in Maternal Foetal Medicine. Fortunately in this instance, after many investigations, we were able to find the rare recessive disorder that both the parents carried causing the death of their two babies. After a harrowing few years of burying their babies, the couple are currently pregnant again, awaiting a prenatal targeted mutation testing which would establish if this foetus is affected or not. We know that there is a 25% chance of this foetus also being affected and this family having to bury a third baby.

“I must struggle with the tension of the two opposing opinions… one arguing that ‘just because we can, does not mean that we should’, and the other stating ‘just because we have not done this before, does not mean that we should not be doing this’.”

Though rare, these recessive conditions grab attention with the often heart-wrenching story of unexpected loss and what could have been avoided with the availability of newer testing modalities. From invasive testing for foetal karyotype, we have raced through Cytogenetic Molecular Arrays to sequencing the foetal exome and to the whole genome. DNA testing of parents and the foetus/neonate (trio testing) is now considered the standard of care for these challenging cases (Schwender 2012). Technological advances have made it possible for us to examine/sequence the whole exome (WES) – the gene coding region (~30,000 genes in the human genome) – or indeed, the entire human genome of 3 billion base pairs (WGS) (Chen 2017, Jelin 2018).

For this particular couple, it was a mutation (a substitution of just one base pair) involving a mitochondrial protein gene which was implicated.

The options to avoid this possibility were:

• not having any more pregnancies, but instead adopting,
• the possibility of using donor sperm or egg,
• in-vitro fertilisation (IVF) with preimplantation genetic diagnosis (PGD) or prenatal invasive testing to confirm the status of the foetus,
• or a three-parent family (UK precedent) with donor egg mitochondria (without nucleus) (Dahiya 2018).

Each of the above management options has its ethical challenges. Instead, the parents decided to conceive spontaneously, requesting early prenatal testing.

There are numerous clinical contexts where the conversation about prenatal carrier screening becomes appropriate. Though the above-mentioned case is rare, there are many other rare recessive disorders which would only become evident through trio testing after an unexplained loss. Moreover, there are several other common conditions where carrier screening is recommended. Recently the media reported on a couple who had lost their baby with Spinal Muscular Atrophy (SMA). The report quotes the mother “We should never have gone through this… No-one should feel this pain. It’s preventable through carrier testing.” (Scott 2018). Many prenatal carrier screening tests (limited and expanded, depending on costs) are being offered by various companies ‘direct to the consumer’.

The framework of virtue ethics may help

The discussion of the ethics behind both prenatal carrier screening and prenatal testing is complex and dealt in published literature (Horn 2018, Appleby 1988, Alderson 2001). As a clinician engaging with parents in their complex grieving and aiding them to find a way forward in a prenatal context, ethical frameworks of principlism (autonomy, beneficence, non-maleficence and justice) or consequentialism are inadequate. Nevertheless, the framework of virtue ethics may help in creating a way forward (Gardiner 2003, Gillon 2015, McCrathy 2003). It is possible that these ethical frameworks will be eroded and overridden as medical practice becomes more ‘protocolised’ and ‘regimented’ by college guidelines and algorithms for management.

The recent RANZCOG statement requires that:
“All couples intending to have children, or who are pregnant, should have a careful family history taken regarding relatives with inherited disorders.¹ Those identified with a family history of inherited disorders should be made aware of the availability of carrier screening for recessive conditions” (RANZCOG 2018).

The recommendations regarding carrier screening for monogenic conditions and populations with specific risk screening programs are also described in the statement.

Options of preimplantation genetic diagnosis, donor gametes, prenatal diagnosis and termination of an affected foetus are intrinsic to peri-conceptional carrier screening. Regardless of the ethical dilemmas of the options above, all of them are possible choices that couples may make under various prenatal circumstances. Prof Wayne Grody (Paediatrics and Human Genetics at UCLA), in an excellent editorial in JAMA, states that implementing large-scale carrier screening programs without adequate thought about its implications can cause more harm than good (Grody 2016). In addition, screening by Non-Invasive Prenatal Testing (NIPT) for various genetic syndromes with combinations of the so-called ‘expanded panels’ is already offered by various companies despite the College position that these are not supported (RANZCOG 2018).

One of the reputed laboratories in Australia reports “no other autosomal aneuploidy detected” despite the fact that the request form is only for the common trisomies on NIPT (T21, 18 and 13). Prenatal or pre-conception carrier screening for SMA, Cystic Fibrosis (CF) and Fragile X is now available in Australia and recommended to be offered to all couples. With the relentless march of medicine and the alliance between business and health, it is inevitable that large-scale expanded prenatal carrier screening and non-invasive exome sequencing of foetuses will soon be offered (Hayward 2018).

However, there is no clarity in prenatal carrier screening or exome sequencing about many of the issues listed below:

• How detailed should informed consent be when discussing prenatal carrier screening and prenatal exome sequencing?
• What and how many conditions need to be offered as carrier screening?
• What are the options parents have, if they are carriers?
• How informed are the parents about possible inadvertent findings in the exome, not related to the pathology being investigated?
• What if doubts about paternity are raised?
• What about:
  – genes that are associated with adult onset illness?
  – genes that may be pre-mutations for disease?
  – genes that have predisposition for neuro-psychological impairments?
  – genes that are cancer-associated?
  – genes that are variants of unknown significance?

So far, we have blindly borrowed all our data from results obtained from testing of children and adults with known pathology and reach our conclusions on prenatal testing where pathology may or may not be present.

The complexity of “shared decision making”

Counselling the parents becomes complex because of the variable expression and penetrance of the genes involved and there is no certainty in many instances as to the actual phenotypic or functional manifestation in the foetus/newborn. In the context of a child or adult, treatments are available and the life of a child or adult is protected by social mores and by law, whereas in the context of the prenatal testing, the pathology is projected, uncertain and the life of the unborn baby is not protected either by social mores or by law.

The very pillars of ethical principles – autonomy, beneficence, non-maleficence and justice – become arguable in the context of prenatal testing, with the unborn child considered legally as a non-entity.

The medical fraternity has found refuge in being non-paternalistic and non-directive in counselling, and the current recommendation is to give the parents all the information from prenatal testing (molecular arrays/WES or WGS) regardless of its nature (pathogenic; unknown or copy number variant) and involve them in ‘Shared decision making’ – thus passing on the burden of knowledge and decision-making to the family. This is symbolically similar to what Pilate did in washing his hands before handing Jesus over for ‘Shared Decision making’ by the mob (Matt 27:24 NIV).

Should all prenatal genetic testing be condemned?

Progress will continue to be made and the cost of prenatal carrier screening and exome sequencing will become cheaper and affordable. More guidelines will invariably make these the standard of care and some unborn children will needlessly have their life terminated from the uncertainty projected/predicted from the prenatal testing. This does not make progress undesirable or the technology wrong. The case discussed above, and many others, have had answers through trio testing, resulting in successful pregnancies with prenatal testing.

Regardless of our persuasion based on ethical or scriptural principles, I would be cautious in condemning all prenatal genetic testing. Christians have not invariably got ethical issues right. Over the centuries, Christianity has found scriptural support for perpetuating what we consider are social injustices, eg. human slavery and apartheid (Early 2008).

I am also reminded that the Church warned Galileo to recant, insisting that the sun revolved around the earth (Wolf 2016). I would certainly not want to hide behind spiritual phraseology and accept that the loss of these innocent babies is God’s will.

I must struggle with the tension of the two opposing opinions expressed in one of our multidisciplinary meetings by two senior consultants: one arguing that “just because we can, does not mean that we should”, and the other stating “just because we have not done this before, does not mean that we should not be doing this”. One raises caution about how and what we do, while the other desires progress without which we would still be in the Dark Ages.

“None of these – justice, love or mercy – may be easy to define in a complex clinical situation. Therein is the challenge of life, and living in a real world with many shades of grey.”

I wholeheartedly agree with Paul Mercer when he says, “A simple scan of Biblical material offers no immediate texts around the ethics of prenatal diagnosis. The ‘eyes to see’ that come with the formation of Christ in us, will take us further” (Mercer 2018).

I continue to find encouragement in the words of Micah, “And what does the LORD require of you? To act justly and to love mercy and to walk humbly with your God.” (Micah 6:8 NIV). None of these – justice, love or mercy – may be easy to define in a complex clinical situation. Therein is the challenge of life, and living in a real world with many shades of grey. My prayer is that ‘my eyes will see’ all the shades of grey in each and every complex clinical situation.

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Acknowledgements

I acknowledge the pain and suffering that many parents go through dealing with the loss of a child. I want to thank my family and colleagues especially Drs Frank Garlick, Kuruvilla George and Jade Lodge who read through my manuscript and gave valuable suggestions.

References

1. Irenaeus of Lyons: http://henrycenter.tiu.edu/2017/04/.irenaeus-creation-the-fathers-two-hands/

Bibliography