Family history of no significance?

[progers]

I have always understood that family history is a good indicator of how one's HCM will progress. The theory is that particular HCM genes run in families, and that some genes are associated with a particularly high incidence of disease progression and/or sudden death. Other genes are associated with benign outcomes. There are even published articles that make this same claim (e.g. ' Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy' by Doolan et al. (2004), as well as the HCM Consensus Document on HCM from 2003).

I was discussing this with my doctor the other month, and he told me that it is becoming apparent that family history is really of no prognostic value in determining things like disease progression. This has me confused, particularly because he was one of the authors of the 2004 paper mentioned above. What does this mean for deciding on who has a pacemaker? I understand the whole genotype versus phenotype explanation, but the logic doesn't make sense.

Anyone have any info on this?

Cheers,

Paul

[Reenie]

I think so far as I know there isn't concrete evidence that whoever has a certain mutation will have a particular set of problems, but there has been speculation that this is the case. I know researchers have been looking at this for some time. If it's true, you would assume those with HCM within the same family would have a similar course of disease. We also know that isn't always true but does seem to have credence. HCM is still an individual disease but I do think that you can look at family history to get a glimpse at what you might be able to expect in your own journey with HCM.

[Midge Rollins]

Even with the genetic testing if you do carry the same gene as another family member, the test does not tell you when, if or what degree of HCM you have. Many people have the gene and do not develop the disease. What Reenie says is interesting. I guess i have not heard that before. Thanks for the info.

[Pam Alexson]

Here is a good snipet..
4. Discussion

In this paper we describe the identification of novel mutations in MYBPC3 and a remarkably high incidence of the 2373insG mutation in the Dutch HCM population. Haplotype analysis of all Dutch probands and those of North American and German families described previously shows that this mutation is a founder mutation originating from the Netherlands. The high prevalence of this mutation and the number of recombination’s that have occurred in the <0.9cm region between MYBPC3 and distal CA repeat markers suggest that this mutation arose many centuries ago, and was introduced into North America by European (Dutch)immigrants. Given the prevalence of HCM, i.e. 0.2% in the general population,1and the frequency of this mutation in the Dutch HCM patient group (23%), one can very roughly estimate that there must be 7360 2373insG carriers in the Netherlands (population 16 millionpeople).

Most of the HCM causing mutations are unique per family and founder effects are described in only a few cases, usually concerning only a few families with the same mutation.12,15–18Only mutations that do not exhibit a high mortality rate before reproductive age can be transmitted and become founder mutations. The strong founder effect of the 2373insG mutation suggests this mutation has mild effects in the first three decades of life, which was indeed noticed in larger families carrying the 2373insG mutation and which has been reported for other MYBPC3 mutations.9–11When symptoms develop however, the phenotype is not mild; at least 29 of the probands had family members that died of SCD.

This insertion at position 2373 in the MYBPC3 gene has been extensively analysed by Moolman et al.13The insertion creates an alternative splice donor site and leads to alternative splicing, skipping of exon 25 and a frameshift after Q791. However, expression of a truncated protein was not detected in affected heart tissue, suggesting that, in this case, HCM is caused by haploinsufficiency. Hypertrophic cardiomyopathy exhibits a wide spectrum in disease onset, manifestation and progression, even between subjects in the same family. Disease development is thought to be influenced by lifestyle, environmental and also genetic influences. Study in a large family with 26 2373insG carriers indicates that polymorphisms in the renin-angiotensin-aldosterone system influence expression of the mutation19and it is likely that additional genes that contribute to phenotypic variability, penetrance and age of onset await identification.

The discovery of a founder mutation with such a high frequency facilitates DNA diagnostics, making cascade screening possible in the near future. A multidisciplinary approach, strict monitoring of pros and cons of this screening and the development of clinical guidelines for testing and follow up of carriers is prerequisites for this large-scale screening.

......Sorry I could not get the link to go through, this article references the The Netherlands study of HCM individuals.

[Pam Alexson]

I found this article interesting about them watching the son who has the gene and some positive signs but not the disease expression yet.... The dad however has the AICD

http://pub.ucsf.edu/magazine/200412/genetic.html


Over and over it is now referred to as "diverse and varied" and the unknown triggers to unique disease expression may play the bigger role in families with HCM and the course the disease takes.

[gfox42]

Let me add a word or two, in the event anyone has trouble wading through the genetics jargon.

Having a gene doesn't, by itself, determine your condition. Short people can have genes that tend to make people tall. There are a couple of ways this can happen. The most obvious is what we call environmental factors: the size you reach depends partly on what you eat, for example. The one that confuses many people, including my students, is this: genes interact with each other. The effect that a particular gene has can actually differ from person to person, because it depends partly on what other genes they have.

The cases most people are taught in science classes are the simple, extreme cases. For example, plants that don't have the genes to make red pigments only have white flowers. But the expression of most genes (that's biology jargon for how genes turn into bodies) in more subtle ways.

If you carry a gene that has been identified as contributing to HCM, it doesn't necessarily mean you will ever experience a single symptom. A large proportion of HCM patients who've been tested for known HCM genes don't seem to have any. This doesn't mean they don't have any -- it almost certainly means that other genes contribute to HCM but aren't yet known. Identifying genetic causes of diseases like HCM is hard work. And very expensive research.

Does family history matter? Clearly, yes: we know that HCM tends to be inherited. But you can also have a brand-new mutation that nobody else in your family carries -- it's what's called bad luck. And since the expression of some of these genes can depend a lot on details of your environment and on the other genes you have, it's possible that you can have a gene that others in your family share, and still be the only one with symptoms of HCM. A different sort of bad luck.

For some kinds of studies, geneticists use a statistic called "heritability." In a rough sense, it describes how well you can predict the offspring's phenotype from the parents'. If a trait has a heritability close to 1, it means that the prediction is almost always perfect; if it has a heritability close to 0, it means that you can't predict it at all. It's pretty clear that HCM's heritability isn't that close to 1, but it's not 0 either.

In some sense, it has to be true that information about the particular mutations in your family should be useful in predicting how you'll do. The question is whether there's enough known about how the disease develops, and about your other genes, to make that information actually useful. I'm not a physician -- I'm a lowly academic biologist -- but I'll bet money that the current state of knowledge is such that it's currently useful for physicians to know in the case of some particular mutations, but not in many others. Which is a complicated way of saying "it depends."

Cheers,
Gordon

[progers]

Lots of good info here, thanks Gordon. Also, Pam you always deliver on the research side of things! (how are you by the way?) So, we can conclude that just because one family member has symptoms doesn't meant you will get symptoms (and vice versa)? Building on this logic, does this also mean that sudden cardiac death, just because it runs in a family, is of no predictive relevance for the insertion of a defib/pacemaker? It's an interesting question, and one that has probably been addressed in research.

Cheers,

Paul

[Cynaburst]

Family history of sudden death IS absolutely one of the factors which is used to determine whether another family member is a candidate for an ICD. If one sibling, for example, has a premature sudden cardiac death, and then it is determined that another sibling carries the gene, then the remaining sibling will almost always be implanted with an ICD.

I think what everyone is saying here about family history is that it is not determinative, but it is certainly a factor. Also, if a gene seems to be affecting a family pretty strongly, then I think that there is enough evidence to suggest that future generations will likely also be affected.

For example, My family has a strong family history of HCM. As far as we know, my grandfather, uncle, father and myself have all been affected. My grandfather (who did have symptoms) and uncle (who had minor symptoms, if at all) died suddenly. My dad has struggled with HCM for many years and now has end stage disease. I have had a myectomy, have an ICD due to v tach on holter, and have had pretty significant symptoms. If my children carry the gene, it would be a pretty good bet that they would also develop HCM and we would be very proactive in trying whatever treatment that was available to prevent the HCM from developing based on the stong presentation in my family.

[gfox42]

Please be careful not to read more into what I said than I intended.

It's certainly true that we can't say that because your parent had HCM (or sudden death from HCM, etc.) you WILL have the same.

But it's also true that there is a "positive correlation" between parent and offspring (or between siblings) for these traits. In other words, it IS possible to predict that if others in your family had sudden death you are LIKELY to as well. All that "heritability less than 1 but greater than 0" means is that these things aren't guaranteed.

If I had a relative who'd had sudden death, I'd be at the Dr's office right now talking about getting an ICD.

In summary, your family history gives the basis for a statistical prediction: you are much more likely to have X or Y if others in your family did. That doesn't mean it is certain that you will have X or Y.

Most of us don't smoke, partly because we know that smoking is likely to cause serious health problems. We know of people who smoke but don't develop those problems. We don't conclude that smoking is therefore safe. Ditto for wearing seat belts.

So let me clarify. Knowing your family history does not predict the development of your symptoms (or lack thereof) with perfect assurance. It can't, for all the reasons I mentioned. That doesn't mean that it's of no value in prediction. It can be quite valuable.

Should you have genetic testing done? I think the answer is that it depends on your situation. If you want to know whether your kids are at serious risk genetic testing can be quite helpful. If you carry a gene known to contribute to HCM you can learn whether they also carry the same gene. On the other hand, if you don't carry any of the genes that have already been identified as causing HCM, but you clearly have HCM, the test isn't going to be very informative about you or your kids. If you don't have kids, the only way you could directly benefit from genetic testing would be if medical treatments could be geared specially to particular genotypes. That's not yet the case, though it may be in the future.

In summary: inheritance is VERY important. We all know this from other evidence. I look a lot like my mother, and have my father's flat feet, among other things. HCM is known to have a large genetic component. But that doesn't mean that you can predict someone's disease with perfect accuracy just from knowing their family history. What can be done is to realize that the family history is meaningful: if you have a family history with lots of obstruction, or sudden death, it would be wrong to conclude that you will certainly have the same, but it would be even more foolish to conclude that it's not likely!

Gordon

[Pam Alexson]

Thanks Paul, I love research and love to see that there are great minds studying HCM ...
I am managing.. thanks for asking. Now will be seeing a urologist hoping my kidneys are going in the right direction still.

Pam

[progers]

Hi Pam. I sometimes think I over research HCM...serves me right for being an academic!

Hi Gordon - I was speaking rhetorically, just trying to work through the logic of this issue, that's all. I will put that question to my HCM specialist when I speak to him next.

Cheers,

Paul