GENEWATCH
 
A COMPLICATED INHERITANCE
By CRG staff - Interview with Harold Cross
 

from GeneWatch 26-4
Aug-Oct 2013

Harold Cross, MD, PhD, began studying genetic disorders in the Amish community of Holmes County, Ohio, in the 1960s and founded the Windows of Hope project to improve Anabaptist communities' access to information about genetics and inherited conditions. He was born into the Amish community of Elkhart County, Indiana.

 

GeneWatch: Certain genetic disorders are more common, sometimes much more common, in some Amish communities. Could you say a bit about the scope of the problem and your work on it?

Harold Cross: We're specifically interested in autosomal recessive disorders. For this sort of disorder, one genetic mutation on one chromosome usually does not cause a disease - you have to inherit the mutation from both sides, which means that both parents contribute the defective gene. That kind of situation, where both parents carry a single copy of the same rare mutation, is primarily present in groups of individuals who tend to marry others who are somewhat related to them, or at least come from the same "founder," as we call it, of a group. This may be nomads in Saudi Arabia, it may be enclaves of families in India or China, but in this country those conditions are met primarily by Amish and also some Mennonite groups, in communities that tend to marry among themselves and admit very few "outside" people. So what you end up having is what we call a "founder effect." Whenever a small group of individuals found a community, the descendants of these founders obviously carry these genes as well. So since there are relatively few founders, generally, that means if the founders had a recessive mutation and the group continues to intermarry and doesn't admit many outside people, it increases the chances that a male and female, each with the same recessive mutation, will meet each other. This is what leads to autosomal recessive diseases.

From a genetics point of view, or a scientific point of view, this provides an opportunity to look for mechanisms of disease, to help us understand biochemical pathways and the nature of health and disease. That's what makes groups like the Amish and the Mennonites useful to study, but of course there are others around the world as well.

Would it make much difference if there were more marriages across different communities within the same faith - say, between an Amish community in Ohio and one in Indiana?

That's a very good question, and the Amish have actually raised that question as well. But here's the scenario, in very broad terms: The first Amish that immigrated settled in eastern Pennsylvania in the 18th century. There was another whole wave that came over in the 19th century, and they tended to skip over eastern Pennsylvania and settle more in western Pennsylvania, and from there they settled in Ohio and Indiana, and in many other communities in other states. So it really doesn't do a whole lot of good, say, for someone in Holmes County (Ohio) to say, "I'm going to go to Indiana to find a wife, someone who's not related to me," because they're probably related as well - the Indiana community came from the same people who founded the Ohio community. The eastern Pennsylvania Old Order Amish seem to be genetically somewhat different. They have different surnames, different blood groups, and to some extent different diseases. But for most of the rest of the Amish, it really doesn't do much good to move to another community, because you're just going to find more relatives there!

Do Amish couples usually look back at family trees before getting married?

Well, they don't really. There's an embedded prohibition against marrying first cousins, so they certainly check that out. Some of them might know they might be second cousins, but for third and fourth cousins, they don't usually check that far back. The information is freely available, there are good genealogical references, but it doesn't usually get checked out. The problem, though, is - OK, let's say you marry your second cousin. What happens is that the progenitors of those second cousins themselves are related in some way, and their parents are related, etc.  The degree of relatedness is cumulative so couples are more closely related than a simple 3 or 4 generation pedigree would suggest. 

So that's where the founder effect comes in.

That's right, all those ancestors were also related to each other. Of course, there are new mutations happening all the time, we all have them; but in general society, the chances of meeting up with someone who has the same rare new mutation is pretty small. That's why most of these recessive diseases are extremely rare, with the exception of an isolated community, where we can find, in some cases, a substantial number of individuals with the same problem.

And one of the things that maintains that founder's effect is that not many people convert to become Amish, right?

That's true, and this is an argument that I like to point out: While groups like the Amish can have a fairly high number of individuals born with autosomal recessive diseases, they're oftentimes fairly local. For example, one disease that we have worked on, that I found in the 1960s, is only found in Holmes County. We've never found an individual outside of Holmes County with this disease. So the chances of somebody coming from outside and contributing that mutation is pretty low, because it seems to be restricted to the Amish themselves.

But having a closed community also excludes other diseases. Take sickle cell anemia: As long as no one who carries that gene enters the Amish community, the Amish will not have sickle cell anemia. And there are many other conditions which the Amish don't have because of this. So it's also a protective mechanism.

You've been working on this since the 1960s. How have you seen this research help Amish communities?

As you say, I've been doing this for forty-some years, and obviously the end result we're looking for is a benefit to the communities. But how do you do that? Well, a lot of people are very grateful to know "this is a genetic defect - it wasn't because I ate the wrong vitamins or vegetables or rode horses too much." There are psychological benefits that come from knowing why your child is the way that he or she is.

But what you'd really like to do is reduce the number of individuals born with severe developmental regression or neuro-degenerative diseases. This can be complicated sometimes because of Amish religious teachings. For example, we could do in utero testing, but it doesn't really matter if you find out that an unborn child has a disease if the parents say, "well, that's God's will, that's the way it's going to be." So that kind of work which is done in the general population really doesn't work for the Amish. Now, one of the things I've observed over the years is that younger generations are much more interested in becoming knowledgeable about some of these things, and they avail themselves of computers. You ought to see the numbers of horse and buggies tied up outside the county libraries! And you go in there, and there are all these Amish young men and women on the computers, looking up stuff. So they're much more informed and more anxious to see what could be done, much more than the older individuals, who tend to say "It's God's will, it's the way it is." So there's an opportunity, and it's something that we're very interested in exploring, mainly for the education of younger couples who are building their families. If you know - and we can test this in both parents - that they each carry the same mutation and have a 25% chance of having a child with this disease, they can decide whether they want to risk it. So we can do that, we can certainly do premarital and later testing to determine whether each parent carries a gene. It's not unlike the big push now among Ashkenazi Jews, encouraging young people to come in before they have kids and get anonymously tested. They don't have to tell you what you carry, but they say "you both have a gene which, if you both pass it on to your children, they will have a disease." And they leave it up to the individual to decide whether they want to do it.

Now, ultimately, I don't want to change the Amish. It's not my business, and we shouldn't interfere with them. But I do think that knowledge is power. We offer free testing to anyone who wants it, and there are some parents who say they want their children tested. Now, what you do with that information is another thing - it doesn't do much good to get tested and find out you have a mutation if you don't also test your partner or prospective partner.

I'm speaking frankly with you here - we're not necessarily promoting any of this - but if we can make information available about transmission of diseases and basic genetics, then hopefully the population will use that to their benefit. But that's a slow going process.

Is there some way of reconciling things like premarital testing with that very important belief in God's will?

We have had meetings with some bishops and community leaders and raised that question: Would people accept this, do they think it's an acceptable thing to do, or is it against their Ordnung. And it's really interesting - I thought there would be a more uniform opinion, but there really isn't. One bishop says, "I leave it up to the families," and another says, "I'm not sure we want to do that, I'm concerned about what it might lead to." So there isn't a uniform opinion on this, but maybe eventually it will be addressed and become part of the discussion.

Again, though, my role in all this is just primarily to tell them what information is out there, what tests can be done, and obviously it's up their own free will to do whatever they want to do.

When you do research within the Amish community and come back and share those results, is it very well received?

Very much so. You know, they're essentially self-insured, they have their own funds they use to help families out, and they're very aware of the burden of genetic diseases on the community and the cost of it. We often get families who find out about what we're doing and ask if we can come do testing for them.

Here is the best example: We discovered, about 7 or 8 years ago, a new mutation that causes hypertrophic cardiomyopathy, a heart condition which can cause sudden death at any age. We found the mutation that causes it, and we began testing for that. In adults, that's a dominant disease, so it's passed along with 50% probability to every child that you have. We've been at this for a few years, trying to identify individuals who carry the mutation, because they're at risk of sudden death. And this has real health benefits - if caught in time, treatment can save your life. Well, it didn't take long until we had people coming out of the woodwork asking to be tested. People are very tuned into heart disease, so this has really resonated in the community.

As a general rule, Amish are very interested in knowing about their genes and the diseases that they cause, and now that we've been working in this community for years - we make a couple trips there every year, and we have some people working there full time - we're getting invited to reunions and special occasions because people want to meet us.               


 
 
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