The New York Times, July 31, 2014
The family seemed to defy the rules of genetics.
When Meriel M. McEntagart, a geneticist at St. George’s University of London, met the family in May 2012, she suspected that three of the children had a rare genetic disorder called Smith-Magenis syndrome. They had many of the symptoms of the disease, such as trouble sleeping through the night. Dr. McEntagart confirmed that diagnosis with a genetic test. The children were all missing an identical chunk of a gene known as RAI1.
One of the children had a different father from the other two, and so the mother could be the only source of their altered gene.
But when Dr. McEntagart ran a standard blood test on the mother, the results were not nearly so straightforward: The woman had a normal version of RAI1.
Dr. McEntagart and her colleagues suspected that the answer to this puzzle was that the mother was a genetic mosaic.
We tend to think of ourselves as having just one set of genetic material, which exists in identical form in every one of our cells. But sometimes, people have two or more significantly different genomes. As our cells divide, some may go through a major mutation. So some individuals end up with groups of cells that have very different DNA from the rest of them.
Dr. McEntagart said that she suspected that the mother she encountered had a normal version of RAI1 in some cells but an altered version in other cells, including her eggs.
“We wanted to understand if there was a way to demonstrate that she was a mosaic,” Dr. McEntagart said.
Dr. McEntagart got wind that researchers at Baylor College of Medicine in Houston were developing new methods for pinpointing mosaics, and they confirmed that the mother was indeed a mosaic. Some of her cells carried the Smith-Magenis syndrome mutation.
Scientists have known about mosaicism for decades, but they’ve studied it mostly on a case-by-case basis. As a result, it has been hard to tell if the kind of mosaicism Dr. McEntagart encountered was a fluke, or if it was common enough to be medically important.
In a study released Thursday in the American Journal of Human Genetics, the Baylor team and its colleagues describe the biggest search for cases in which mosaic parents passed down disease-causing mutations to their children. It turns out to be far from a fluke.
“This happens a surprising amount of the time,” said Chad A. Shaw, a co-author of the new study.
Michael Snyder, a geneticist at Stanford University who was not involved in the study, said it showed that mosaicism could have a significant effect on not just people’s own health, but on their children as well.
“We will have to be on the lookout for these types of events,” he said.
In order to solve the Smith-Magenis mystery, Dr. Shaw and his colleagues had to create a sensitive test that could distinguish between normal blood cells and cells with the altered RAI1 gene.
First, they examined the DNA of the three children and determined the precise sequence of the DNA surrounding the missing chunk of the RAI1 gene. Then they could look for the same sequence in the mother’s blood cells.
The majority of the mother’s blood cells had intact copies of the RAI1 gene, the scientists found. But 25 percent of the cells lacked the same piece that was missing from the children’s genes.
The scientists argue that there’s only way to explain these strange results: The mother became a mosaic when she was a tiny clump of embryonic cells.
As the cells divided, one of them lost part of its RAI1 gene. It then passed down the mutation to subsequent generations of cells. Only later did the embryo change from identical cells into different tissues. As a result, the line of cells with the defective RAI1 gene gave rise to some of the mother’s eggs, some of her blood and perhaps some of her other tissues as well.
Having developed this method for detecting mosaic parents, the scientists decided to conduct a larger study to see how common mosaicism is. They began searching for families that would be willing to participate. Each family had to have a child that had a genetic disorder caused by the deletion of some DNA. And they had to have taken a standard genetic test that had failed to find the deletion in either parent’s genes.
Eventually, the scientists were able to study 100 families. They searched for cases in which the parents were mosaics and had the same mutation as their children.
“We thought going into this study we’d find maybe one or two if we were lucky,” said Ian M. Campbell, the lead author of the study. “And then we found four.”
Mr. Campbell and his colleagues were surprised to find that many mosaic parents. And they suspect that the true number of mosaics among the 100 families was even higher. For one thing, their method lets them detect only genetic deletions, but other kinds of mutations can cause genetic disorders, too.
James R. Lupski, another co-author on the study, points to a second limitation of the study. “It only tells you what you see in the blood,” he said. If the scientists could have examined muscle or other tissues, they might have found even more mosaic cells.
The results suggest that some people can have serious genetic diseases without any symptoms. That’s because they have the defective version of a gene in only some of their cells, and their other cells compensate for them.
But such people are unknowingly at risk of having children with full-blown versions of their diseases, if the mutation appears in their reproductive cells. Dr. Lupski said that as technology improved, clinical geneticists should test people for this hidden risk.
“Couples are going to want some answers,” he said.
Copyright 2014 The New York Times Company. Reprinted with permission.