TABLE 2.
Categories and types of uncertainties
| Category ‐ uncertainty related to… | Type of uncertainty | Example quote |
|---|---|---|
| Incomplete knowledge | Pathogenicity and VUSs | ‘It is very often that we find de novo variants, that might be pathogenic, but in a gene that does not have a known significance’. Denmark 2, clinical laboratory geneticist |
| ‘And the other group would be total novel findings where we find regions that are not—there's not a lot of clinical information about the copy number changes involved, but they're very novel in terms of the data sets that we look at, so they may be quite benign, they might be pathogenic—we're unclear’. Australia 4, clinical scientist | ||
| Gene‐disease correlations | ‘We found a deletion of a gene that is very important for the energy conversion inside the brain…but we do not know if this gene can cause illness because we never seen this before’ Denmark 4, geneticist | |
| ‘If you have a gene which is disease associated but the spectrum of mutations does not include large CNVs, that would really be an uncertainty…..if only missense mutations have been found in that gene correlated to disease and then you find a CNV covering the whole gene, that would be uncertain’ Sweden 4, clinical scientist | ||
| How a genetic anomaly presents prenatally | ‘So we've had situations where we're just not sure how a condition which we know quite clearly the phenotype, in the postnatal setting, we just don't know how that's going to look on the scan, because there's not enough information about that condition in the prenatal setting’. Singapore 2, paediatrician | |
| ‘I'm well aware from the Page study where there's cases, for example, Sotos syndrome where they presented prenatally with a small head, microcephaly, whereas actually the condition postnatally is associated with the opposite of that, macrocephaly’ UK 6, clinical scientist | ||
| ‘There is often no phenotype to hold it up against, or at least a very flimsy one. In week 12 you may know if there is a big nuchal fold. The rest is yet too small for you to see it, so it does make a special challenge in relation to the prenatal’. Denmark 4, geneticist | ||
| Unexpected findings | Incidental findings | ‘Previously, we had several of those cases where we had a minor ultrasound abnormality and we find Cri‐du‐Chat. I think that's quite common’ Sweden 4, clinical scientist |
| ‘Recently, I saw a couple with a baby with a 15q11.2 microdeletion, and I mean we know that—and that was just incidental. It was incidentally picked up when they were being evaluated for risk of Turner syndrome. And there was no family history of that’ Singapore 2, paediatrician | ||
| ‘I had a case in which we found a de novo variant that caused a fatal disease. It was a foetus that was dead intrauterine and had malformations… But I find out that the foetus is also deaf. It has two variants in the ‘deaf gene’ and both parents are carriers. And then I find out that the mother also has a variant in a large ‘heart gene’, so she may also be carrier of a heart disease’. Denmark 4, geneticist | ||
| Secondary (additional‐looked for) findings | ‘Like a BRCA gene—that would not be reported prenatally if it is not asked for. If it is known in the family we would report it, if it is asked’. Sweden 4, clinical scientist | |
| Technology | Technical validity of the result | ‘Things that are too small for microarray we won't pick up, yeah, there's promotive variants, so areas around the promotor region of the gene, they're not included in an exome as well. Large indels—so when I'm saying large, I'm saying like over about 30/40 base pairs—the sensitivity of the next generation sequencing because we're using short reads, that also goes down, so there's quite a lot of variants we will miss and we won't get 100% coverage for every single gene as well, so there's a lot we'll still miss’ UK6, clinical scientist |
| ‘Prenatally you rely on the CVS or amnio, and especially amnio's, we might not get as much DNA. So you might be restricted by how much material you have, and obviously that might lead to suboptimal result. Plus other technical problems like maternal cell contamination and things like that’. UK 1, clinical scientist | ||
| ‘We've had samples of poor quality, maternal contamination we can't analyse, haven't met our criteria for quality thresholds. Doesn't happen very often. If possible we rerun the sample or use another technique’. Sweden 5, clinical scientist | ||
| Possible incomplete result | ‘If I find a mutation, find a pathogenic mutation in the gene that matches the phenotype, but I don't have a second mutation. Then I will report it anyway, because the second mutation may be somewhere I haven't seen it’. The Netherlands 3, laboratory specialist in clinical genetics | |
| Condition | Incomplete penetrance | ‘The other big category of uncertainty we come across is the susceptibility risk, so the autism susceptibility loci, the neuro susceptibility loci where you do see the variant in healthy individuals as well’. Singapore 3, geneticist |
| ‘Something like a DiGeorge deletion, we have enough evidence on that to know that it's got incomplete penetrance, but also to know that if you see it in a foetus with an abnormal heart, that that is going to be the cause. But then you see it in the next foetus, it doesn't have an abnormal heart. Doesn't mean they're not going to develop one’. UK 2, clinical scientist | ||
| Variable expression variants | ‘Even if you've got a known microdeletion, I don't know, something like Phelan‐McDermid syndrome or something like that, there's still quite a wide variation in terms of the degree of learning problems or other things that might crop up like epilepsy and so forth and you can't, you know, it's hard even with a small baby to say “this is what's going to happen”’ UK 4, geneticist | |
| ‘So the same variant can express or in very different ways in different people so we could see a very severe prenatal and it could be severe when they're born, OI is quite a common one where you can see different phenotypes. We've had another one where we had a severe scan for OI and we found mum to be affected and she didn't know she had it but actually when they looked at the clinical history, she'd had quite a few fractures’. UK 6, clinical scientist | ||
| Clinical utility | Diagnostic yield |
Interviewer: ‘And so what do you think are the main uncertainties in prenatal genomics today?’ |
| Interviewee: ‘I think that the extent to which like the yield is greater than the testing we currently have in terms of the, the certainty of finding something that would explain a particular, you know, risk or condition’. Australia 1, obstetrician | ||
| ‘I usually say that we find something in approximately half of the severely affected ones. The more affected the child or fetus is, the more likely we are to find something. But I have also been dealing with some really difficult children and fetuses, where we did not find the variant’. Denmark 3, clinical geneticist |
Note: Categories and types of uncertainty taken from a manuscript currently in preparation by Klapwijk et al.
Abbreviation: CNV, copy number variation; VUS, variants of uncertain significance.