Monday, 11 February 2013

Genetics of cardiomyopathies: it's not easy...

Congratulation to Luis Lopes (PhD at the UCL Heart Hospital) who just published his paper (open access in the Journal of Medical Genetics) on a high throughput sequencing screen of a cohort of hypertrophic cardiomyopathy (HCM) patients. Luis (and others, including me) scanned 41 genes either known or candidates for being involved in more than 200 HCM cases and used these data to infer what variants are likely to be causal, and with what level of confidence.

Genetics of inherited cardiac disorders are really complex
This scan highlights the complexity associated with interpreting these data. The issue is that quite clearly not all of the likely causal variants are fully penetrant (ie. the disease may happen, but definitely not systematically). Relatively late onset is also not helping out the interpretation. In addition some of the associated genes are quite polymorphic.  The literature has reported plenty of variants associated with HCM but it is hard to know what to do with these, and I suspect that many false positive have been published.

Lastly, it is plausible that not one but multiple variants, some common some rare, act together to define the phenotype and the disease outcome. We will need incredibly large panels to dissect this complexity. I am not completely convinced by this hypothesis, as the disease may show variable outcome due to factors what have nothing to do with genetics, but this is plausible.

The attitude of cardiologists toward genetic diagnosis is changing
This paper would definitely benefit from showing the stream of review, because it was not easy getting it published. Some of the comments were fair and I am in no way arguing that the reviews missed the point. But, while I am rather new to this disease area, my experience with this paper and my reading of the literature suggests that there is a bit of a turning point: in the past, clinicians have often relied on large pedigrees to obtain very reliable evidence that a variant is causal. While this is a worthy approach, it is often impractical in a clinical context, simply because relatives may not be available or the infrastructure of going through the cascade testing may simply be too complicated.

My point is that to be we need to be able to make statements on the basis of what we find in a single case if we want it to be relevant in the clinic. And that must mean not being completely sure in some cases, and being comfortable making probabilistic statements (such as: "on the basis of the data we see, we estimate that this variant is causing the disease with 80% probability").

Clinicians are, of course, not always happy with uncertainty. It's never very satisfying to tell a patient that we cannot be sure. But this is also not unusual: doctors always need to deal with "maybe" when making decisions. It is perhaps less accepted when it comes to genetic diagnosis because we have in mind a very deterministic view of what genetics can do. But uncertainty is unavoidable, so we will have to deal with it.

Last comment: thank you to the UK10K project
The control samples for this paper were provided by the UK10K, which is great because we need large panels of well matched and well phenotyped sequenced samples to understand what is going on in cases. I am pretty sure that there will be quite a few papers using the UK10K data as controls in the near future. Studies like ours would not be possible without these. As the sample size is growing and the phenotyping becomes more thorough, we plan to publish more on this theme and we will reliably continue using the UK10K as a ressource for controls. I am excited by the prospect of these data becoming readily available (which is not quite the case yet I think, as we had to fill a data acces request).

Friday, 1 February 2013

Occult macular dystrophy: neither Mendelian nor complex, but somewhere in between

With this first post I want to briefly discuss a recently published paper, led by Alice Davidson (UCL Institute of Ophthalmology). This is a nice paper with two stories related to two different eye diseases, with one of them intriguing enough to motivate this post.

The main story: RP1L1 and retinitis pigmentosa

This paper started as a study of the genetics of retinitis pigmentosa (RP). As an aside, RP is an incredibly complex disease with a ridiculously long list of associated genes, each (or at least most) in a Mendelian type manner. In fact, it is probably fair to say that after the brain the eye must be the most complex human organ, at least based on the incredibly complex genetic architecture of these developmental traits.

So, in this study, exome sequencing in a RP patient identified a homozygous loss-of-function variant in a massive candidate gene (owing to homology with another RP gene). So it is quite certain that we have found yet again a novel gene for RP, which is the key finding of the paper.

The second story: occult macular dystrophy

Owing to previous reports of association between RP1L1 variants and another eye disease called   occult macular dystrophy (OCMD), Alice also scanned this gene in a cohort of 28 OCMD case. The results were convincing and consistent with previous work: 5 out of 28 harboured the same rare variant (pArg45Trp) which had been reported before in a Japanese study of 3 OCMD families (Akahori et al., 2010). In contrast the NHLBI exome sequencing dataset only reports one pArg45Trp call in more than 5,000 individuals. So there is no doubt that pArg45Trp is associated with OCMD. And we found other rare variants in this cohort, together explaining probably 9/28 cases.

Occult macular dystrophy is not a simple Mendelian disease

So far so good. But the story became rapidly more complex. Intriguingly, we found in the family of these probands 9 patients with the same RP1L1 clearly causal variants but unaffected (and old enough to have potentially developed the disease). So the RP1L1 variants are probably not fully penetrant (i.e. being a carrier does not mean one will develop the disease). As pointed out above, we also found 19/28 OCMD cases without any RP1L1 variants. SO RP1L1 is neither sufficient nor necessary to cause OCMD, in spite of the massive association.

A middle ground between complex and Mendelian?

The emerging picture is that OCMD is half-way between a complex multi-factorial trait and a Mendelian one: there are very strongly associated variants in RP1L1, almost like a Mendelian trait, but this is not quite enough to explain the heritability that we observe. Nevertheless, the genetic architecture may still be simple enough to obtain in the future a more thorough, if not complete, dissection of the trait.

Now is that a common situation?  I suspect it really depends on the disease field but it's definitely unusual for me. Cardiologists who work with diseases like hypertrophic cardiomyopathy are very familiar with these non fully penetrant variants and these complicated pedigrees that do not look fully Mendelian. But in my past experience I have mostly worked on Mendelian disorders with a very clear pattern of inheritance, or alternatively very complex multifactorial traits (like type 1 diabetes). It is somewhat rare for me to see such disorders with an intriguing architecture but perhaps simple enough to solve fully in the future, with the help of modern DNA sequencing technologies.

What next?

So where do we go from this point? As mentioned earlier in this post, it may be possible to further characterise the architecture of OCMD. We are working toward that (with some support from Fight for Sight), by sequencing additional cases without detected RP1L1 variants. We'll see how far we can go with this but I would hope that these intermediate-complexity traits will eventually give us insights into more complex ones. Indeed, it will probably be easier to dissect the role of genetics and environment for diseases like OCMD than for much more complex traits.