When a mutation does not lead to a disease

The reverse side of personal genomics

Dmitry Ryder, XX2 century

What began in the summer as a scientific project soon turned into a family medical crisis for geneticist Heidi Rehm. In July, she ordered a DNA sequencing test for her 14-year-old daughter, hoping to find a genetic explanation for why one of the girl's adult teeth did not grow. Instead, the mother and daughter discovered that they were both carriers of a genetic mutation associated with dilated cardiomyopathy – a cardiomuscular abnormality that can lead to sudden death, especially in adults.

After consulting with a cardiologist and researching her family's mutations, which were found only in people with diagnosed cardiomyopathy, Rem discovered that the mutation may not be as deadly as it first seemed. Her story shows what a long way genetic sequencing still has to go before it becomes a routine part of medicine. Although scientists use sequencing to save the lives of sick people, many still wonder if it helps those who have not been diagnosed.

Since most of the genes associated with the disease have been found in sick people and their families, geneticists do not have an accurate idea of how mutations behave in people who do not appear to be clearly ill. "Right now, this is a hot topic of discussion," said Robert Green, a geneticist at Brigham and Women's Hospital in Boston, Massachusetts. "Many people are deeply concerned that widespread screening of supposedly healthy people can actually harm."

Green is the organizer of the Understand Your Genome conference, held on November 15 in Boston, which was attended by scientists and doctors. About 40 of the 140 participants paid $2,900 each to Illumina in San Diego, California, to sequence the protein-coding regions of their genomes - so they themselves are concerned about the misdiagnosis.

Concerns about the potential harm of sequencing the genomes of healthy people are growing as more and more new companies compete to provide such services to the masses.

In August, researchers reported that the average person is a carrier of about 54 genetic mutations that are considered fatal, but do not seem to cause harm to health. As a result, doctors do not know what to say to healthy people who are carriers of these mutations.

According to Isaac Kohane, a physician and bioinformatics specialist from Harvard Medical School in Boston, some people received incorrect information. He led a team that reported in August that some African–Americans were mistakenly told a decade ago that they were carriers of genetic mutations that increase the risk of hypertrophic cardiomyopathy, a potentially fatal thickening of the heart muscle. Geneticists later sequenced the genomes of many more African Americans, and realized that genetic variants were too common in this population group to be harmful.

"We are really going through a perfect storm of insufficient data and insufficient competence," Kohane said, adding that doctors are not yet ready to process the results of this type of genetic tests.

Green and other researchers are trying to eliminate the lack of information. In the course of the study, an article about which was published on November 9 in Science Translational Medicine (Hayden, The flip side of personal genomics: When a mutation doesn't spell disease, see the links in the note), Green's team found that people who are carriers of genetic variants associated with heart disease and cancer have from four up to six times more likely to develop these diseases, regardless of their family medical history. Green believes that the study is of great importance because it is one of the first cases when scientists know how much a mutation can increase the risk of the disease in a family without a history of this disease.

"I often find myself in a situation where I'm sitting with my family and they ask, 'How much does this increase the risk of getting sick?“,– Green said. "We have practically no data on the population as a whole."

Rem faced exactly such a situation when she found out about the mutation. This mutation leads to the switching of one DNA base to another in the MYH7 gene encoding the heart muscle protein (myosin), and has been observed only in patients with this disease.

When Rem looked into medical reports on people with the same mutation variant, she discovered that it does occur in families with cardiomyopathy. But she also discovered that her own mother is also a carrier of this variant, and at the same time has a normally functioning heart, just like Rem herself. This suggests that the variant has what geneticists call incomplete penetrance (frequency and probability of gene manifestation): it can cause serious illness in some families, but is harmless in the case of others.

It is not yet clear what Rem and her daughter should do with this information. Rem's daughter has not yet had a heart check, because the symptoms of cardiomyopathy, as a rule, do not manifest until adulthood. But she is concerned about the girl's future.

If her daughter's medical record states that she carries a potentially fatal genetic mutation, then she may not be able to buy life, health or long-term disability insurance because she may be considered a high-risk client. The election of Donald Trump as president of the United States also affects the Rem, because Trump promised to repeal Obamacare, the American health care law requiring insurers to offer insurance coverage for people with diagnosed diseases.

"It's very likely that it will be used against her if Trump repeals Obamacare," Rem suggested.

Rem added, however, that she and her daughter don't care about their own health. She will probably be checked by a cardiologist every few years, but does not expect that the discovery of the mutation will change her lifestyle. "People have dealt with uncertainty all the time, and they tend to deal with it pretty well," she said.

Personal genomics is a branch of genomics related to the sequencing and analysis of the human genome. After decoding the genotype, it can be analyzed using published literature to determine the probability of disease risk. Automated sequencing increased the speed and lowered the cost, which made it possible to offer genetic testing to consumers.

Genetic information can allow doctors to adjust procedures to a specific patient, in order to increase the effectiveness of the drug and minimize side effects.

The risk of diseases can be calculated on the basis of genetic markers and genome-wide search for associations for common diseases that are multiple heritable and in assessing which it is necessary to take into account the interaction of genes with the environment.

Portal "Eternal youth" http://vechnayamolodost.ru  21.11.2016