Case 1: Wilson’s disease and reporting of carrier status

Wilson’s disease is an autosomal recessive disorder of copper metabolism which, left untreated, can cause organ damage, meaning prompt identification of affected individuals is important. The case presenter reported disagreement between different laboratories which she consulted for guidance, and the referring clinician (a paediatrician) about whether to report the carrier status for two siblings (aged 7 and 15) of an affected proband. While these siblings could be reassured they were not themselves at risk of developing Wilson’s disease, they could still have an increased risk of having a child with the disorder (depending on whether their partner was also a carrier). The testing laboratory disclosed the 15-year old’s carrier status on the assumption that they had provided their own consent for testing, yet did not disclose the 7-year old’s carrier status arguing that individual could provide their own consent in the future. The fact that the reporting of the carrier status in the two siblings was being handled differently was an issue for the team.[iii] With respect to the 7-year old’s result, the testing laboratory intended to report that Wilson’s disease was excluded, but not disclose whether the child was a carrier. However, the paediatrician thought carrier status should be reported, as did the clinical geneticist, whose view was that that the possibility of a carrier status result should be raised with the family during consent for testing. This conflicted with approaches taken by other laboratories (with whom the case presenter had consulted as part of her decision-making) which would not make a carrier status finding explicit in the main body of the report, but put it further down the report such as in the laboratory analysis genotype box.

Group discussion of this case

Meeting attendees responded echoed the presenter’s concern that patient reports should be issued and interpreted in consistent ways, and reflected on how different referral and reporting pathways (eg, direct reporting of results to electronic health records) could change the extent to which they felt responsible for ensuring appropriate interpretation. For example, the clinical scientist quoted below described how the involvement of non-genetic/genomic clinicians would change their confidence in reporting carrier status:

at the moment we do treat mainstream clinicians differently to clinical genetic services. If we got a referral from [a] GC [genetic counsellor] and it was for a seven year-old and they said [please report] carrier status, we wouldn’t hesitate to report the carrier status back because we would assume that they’ve been properly consented. But we wouldn’t do that for mainstreaming. (l1343-7)

Attendees questioned how much interpretation work non-specialist clinicians and patients could be expected to do for themselves, one attendee noting that demands on paediatric services might mean there is still a risk that the family in Case 1 would not be adequately counselled or followed up about the clinical significance of a carrier test result (l1553–7). This highlights a concern about where responsibility should reside: who should be responsible for following up families or individuals with genetic results, especially when mainstream services are not set up to follow up future risks. Importantly, discussions indicated that discharging this responsibility was more complicated than genetic/genomic specialists making written reports or letters more detailed or explicit, one attendee noting how clinical consultation in the mainstream setting can also change the meaning of written information:

we [genetic specialists] have all of the skills to, and the knowledge to counsel these patients, but… [thinking about] the mainstream clinicians, sometimes even if you document it in your letter, at the time you feel that they’re well understood, but the message received or perhaps repeated to a family member or another clinician is not the precise genetic counselling language that we would use, and that message can get changed when it’s repeated. (l1775–80)

Case 2: PGT-M using a VUS result for reproductive decision-making

The case concerned a consanguineous couple whose first child had global developmental delay and multiple congenital anomalies and had died in early childhood.

The child had been found to have two variants of uncertain significance in genes which were potentially in keeping with the child’s phenotype. One was a de novo heterozygous variant associated with an autosomal dominant condition, the other was a homozygous variant (inherited from each parent) associated with an autosomal recessive condition. The couple wished to have another child through preimplantation genetic testing; however, this was declined by the state healthcare laboratory/clinic due to the uncertain nature of the variants identified. A commercial lab had agreed to undertake PGT-M for these VUS, on the basis that their exclusion might be of some value. However, this testing resulted in the couple losing the ‘uncertain’ meaning from the VUS term—they were given the impression that this testing was significant and would ‘avoid [them] having another affected child’.

The state healthcare laboratory/clinic which held a sample of DNA from the deceased child refused to release the sample to the parents to be used in PGT-M by the commercial laboratory on grounds that there was no clinical utility for VUS testing. Discussions highlighted that the motive for withholding access to the sample was seen as obstructive by the parents.

Group discussion of this case

Ethical issues in this case centre on suggestions to use a VUS to exclude putative diagnoses in future offspring. Meeting attendees discussed the caution needed in being tempted to ‘turn data into information prematurely’. This reflects the judgement needed when deciding whether to maintain an approach consistent with current guidelines to conventionally less actionable categories of genomic data for example, VUSs in the clinic, or to derive more clinically significant or actionable findings where the clinical context or phenotype is driving this.

While these developments in technology have been helpful reducing the length of the ‘diagnostic odyssey’ there was concern about genomics being seen as providing clinical answers it often could not provide. Some raised concerns that genetic/genomic technologies might lead to a new type of ‘odyssey’. Later in the discussion, another attendee described this as a tension between the desire for genomic results to be clinically useful yet being cautious of the impact of misinterpretation:

there’s this kind of to and fro, like you really want to find an answer for your patient, but you don’t want to give them the wrong answer. But because you really want to give an answer to your patient, you kind of are slightly more invested in [interpreting] these slightly woolly variants [as possibly significant] than the lab are. (l1006–9)

This highlights the importance of context and clinical presentation when interpreting genomic results and therefore how the perspective and responsibility of those generating and interpreting these results is a significant ethical factor.

Case 3: echogenic bowel finding used for extended carrier testing for CF

A geneticist presented two cases in two different pregnancies with different practices on finding echogenic bowel at the 20-week anomaly scan.15 [iv]

In the first case, parental testing revealed the mother was a carrier for a variant in the CF gene, which was also detected by amniocentesis in the fetus. The father did not carry a common CF variant but as rare variants had not been excluded, there was still a residual risk that the fetus might have CF. While the clinical geneticist wanted to offer extended CF carrier testing to the father, the laboratory commissioned with doing the test thought this would be a poor use of resources. However, another laboratory then agreed to offer this extended testing. In a second case, where again, only one parent was found to be a carrier following testing of common CF variants, more extensive testing was available but the obstetrician decided not to pass this offer on to the parent, possibly as a result of their experience in the first case.

These two cases raised a number of ethical issues. The team was uncertain about whether to offer extended CF carrier testing because of a low chance of finding carrier status through extended testing and scarce resources. Second, it was not clear how to interpret a VUS from extended testing and, whether CF prediction was clear enough to offer late termination on the grounds of fetal disability.[v] The case presenter then raised the issue of varying degrees of consensus between different clinical genetics centres and laboratories with respect to offering extended testing. She suggested that variation was perhaps becoming more apparent since the reorganisation of labs into different GLHs. The presenter argued that this variation could lead to systemic inequity in patient treatment and wanted to ensure “that we’ve got a very clear sort of protocol and policy within our department and with the lab.” (l1903–5)

Group discussion of this case

In discussions, the solution of consistency and standardisation (usually by producing written materials like guidelines) was proposed to address the ethical issues arising. For example, the presenter of Case 1 (a clinical laboratory scientist) proposed the following measures:

Really, really important that we need consistency across the labs [about routinely reporting carrier status] because even within our GLH we were doing different things, so it’s really important that we have guidelines and then we agree what we’re doing. (l1351–3)

This was echoed by other calls for protocols and ‘unambiguous policy for labs to be able to standardise across the UK’, and for ‘agreed principles [to be] applied uniformly’ across mainstream, clinical genetics and the spectrum of genetic testing (l1097ff).