The Genie’s Out of the Bottle

Genetic testing in the 21st century

From the Human Genome Project to TV medical and crime shows, to an evergrowing list of genetic tests purported to diagnose diseases, trace your ancestry or predict your future, DNA seems to be the subject of the day.

Even those who choose not to undergo testing find it hard to ignore. Whether or not to get tested is a personal decision. But since the DNA testing genie isn’t going back in the bottle, it’s a good idea to get to know him.

Q: What is genetic testing?

Genetic testing is an examination of genetic material — usually DNA but occasionally its chemical cousin, RNA — to detect changes from the usual sequences of chemicals. Some changes (mutations) in a DNA sequence, or missing or extra pieces of a sequence, can cause a disease, increase or decrease the risk of developing a disease, or put someone at risk for passing the disease to future children (“carrier”). Genetic tests can be performed on blood, saliva, skin or other cells.

Q: Why should I consider genetic testing?

A genetic test often can confirm or refute a diagnosis, which may help people with decisions about their own or their child’s medical care or other matters. Test results often help people make decisions about having children.

“We don’t want to label people,” says Shawna Feely, a genetic counselor associated with the MDA clinic at Wayne State University in Detroit, “but there is some comfort to knowing what’s going on.” She’s had patients say with relief, “People always thought I was lazy,” when a muscle disease is finally diagnosed that gives a reason for their exercise intolerance.

In addition, therapies are now being developed, such as for Duchenne and Becker muscular dystrophies (DMD and BMD), that target specific gene mutations, lending a whole new dimension to genetic testing — eligibility for treatment.

For instance, an experimental DMD/BMD medication called PTC124 targets a particular type of mutation called a premature stop codon. An experimental DMD/BMD treatment strategy called exon skipping targets specific sections of DNA where a mutation is located. Knowing a person’s exact genetic mutation would indicate whether or not he might benefit from either of these treatments if they become available.

On the other hand, says Feely, test results can have an unwelcome emotional impact, be distressingly inconclusive, or raise concerns about being discriminated against.

Q: Can genetic testing give me or my child a firm diagnosis?

Genes are strings of DNA, a compound that contains the nucleic acids adenine (red) and thymine (green), stuck to each other; and guanine (blue) and cytosine (yellow), stuck to each other, in a particular order. A missing, extra or changed nucleic acid sequence can (but doesn’t always) cause a genetic disease. For more about DNA and inheritance, see “Facts About Genetics and Neuromuscular Diseases.”

Often, yes, although not always. Some tests don’t examine the entire gene and may miss the part that’s flawed in your DNA. Sometimes a variation in a gene is identified, but no one is certain whether it’s actually disease-causing or whether it’s just a harmless variation. In the second case, the cause of the disease lies elsewhere.

“We look to see if the change reported is a known mutation or what we call a ‘variant of unknown significance,’” Feely says. “When I see there’s a variant, I investigate a little bit more. Based on all the different possibilities, tests can be very complicated, and they can be frustrating to people and to the physician ordering the test.”

Although you often hear people say they do or don’t “have the gene” for a condition, a genetic test will seldom tell you that you do or don’t have a specific gene. In almost all cases, a person with a genetic disease has exactly the same number of genes as anyone else; it’s an abnormality in the chemical sequence of a gene’s DNA, or a missing or added part of the gene, that usually causes a disease. In a few cases, such as spinal muscular atrophy, a gene can be missing entirely. In a few others, such as one form of Charcot-Marie-Tooth disease, a gene can be duplicated.

Q: Can a genetic test predict how fast a disease will progress or what symptoms it will cause?

Only very roughly and often not at all. Many factors, ranging from environmental exposures to the DNA sequences of genes remote from the primary diseaserelated gene, can affect the severity of a genetic disease or even whether it manifests at all.

A modifying factor has been noted, for instance, in Duchenne and Becker muscular dystrophies (DMD and BMD). Mutations in the X-chromosome gene for the dystrophin protein can cause DMD, a severely disabling disease, or the less severe BMD. DNA testing can reveal the precise area of the dystrophin gene that’s mutated, and that usually can predict (at least roughly) whether the disease will follow a DMD-like or BMD-like course. But not always.

An additional mutation in a chromosome-12 gene for the protein known as myogenic factor 6 appears to make the consequences of a Becker-type dystrophin mutation almost as serious as those of a Duchennetype dystrophin mutation. Myogenic factor 6 may be only one of several genes that can modify disease severity in the presence of a dystrophin mutation.

In spinal muscular atrophy (SMA), the number of copies of a gene known as SMN2 is highly correlated with disease severity. (Numbers of SMN2 genes vary in the general population.) People with mutated or missing SMN1 genes and three or four SMN2 genes generally have a milder SMA disease course than those with only one or two SMN2 genes.

In addition, levels of a protein known as plastin 3 have such a dramatic effect that they apparently can determine whether or not SMA develops at all, at least in females.

Q: My son had tests for genetic diseases when he was a newborn and they didn’t show anything wrong. Now we’ve learned he has Charcot-Marie-Tooth disease. Why didn’t they pick this up when he was born?

Many people believe “newborn screening” will identify all or most genetic disorders. Nothing could be further from the truth. There are thousands of genetic disorders, and most U.S. states mandate large-scale newborn screening for only a few of them.

The number of conditions screened for in newborns varies from state to state. In 2006, the American College of Medical Genetics (ACMG) released guidelines for state newborn screening programs that recommended mandatory screening for 29 conditions, none of which were neuromuscular diseases.

The criteria the ACMG used for recommending mandatory testing for certain diseases included the availability of an accurate test for the condition; the ability to identify the disorder within 24 to 48 hours after birth, at which time it would not ordinarily be detected without the test; and evidence that early detection would result in timely intervention and effective treatment.

The ACMG’s list of recommended tests will change as new diagnostic techniques and treatments become available. For example, the 2006 approval of Myozyme by the U.S. Food and Drug Administration for the treatment of the neuromuscular condition Pompe disease came too late to make the ACMG guidelines of mandated tests, even though it meets the criteria.

At the time the 2006 list was compiled, the only neuromuscular disease to receive even conditional consideration for newborn screening was the metabolic muscle disorder carnitine palmityl transferase 2 deficiency (CPT2). Doctors said a CPT2 test should be done if it was useful in diagnosing one of the 29 conditions definitely recommended for newborn screening, as sometimes it’s necessary to rule out one condition before making a definitive diagnosis of another.

Q: Can a genetic test result make it hard for me to get insurance or employment?

This was a major concern in the United States until recently, but is less concerning now, thanks to the passage of the Genetic Information Nondiscrimination Act (GINA) on May 21, 2008. MDA was a staunch supporter of GINA, which protects Americans from discrimination by health insurers or employers based on genetic information.

Testing for a genetic disease in children without symptoms is controversial.Specifically, GINA prohibits health insurers from using a person’s genetic information in determining coverage eligibility or premiums; prohibits an insurer from requesting or requiring someone to undergo a genetic test; prohibits employers from using genetic information in making employment decisions, such as hiring, firing or job assignments; and prohibits employers from requesting, requiring or purchasing genetic information.

However, GINA applies only to health insurance and doesn’t say anything about life, disability or long-term care insurers. It doesn’t prohibit health insurers from taking into account current health status, and it doesn’t apply to the military.

Q: Will the results of my genetic test be kept confidential?

In the United States, all medical information, including results of genetic tests, is protected by HIPAA (the Health Insurance Portability and Accountability Act), which became law in 1996. The HIPAA-mandated Privacy Rule became effective in 2001. The rule requires health care providers to protect personally identifiable medical-test results and other records from anyone other than the patient. Records are available to a person or organization that the patient specifically designates, or to another health care provider who is treating the patient.

Feely says health care professionals are bound by patient confidentiality and shouldn’t disclose any information without the patient’s permission.

Q: Should children be tested for a genetic disease that runs in the family if they don’t have any symptoms?

This is among the most controversial issues in genetic testing. When genetic testing on a large scale first became a reality in the early 1990s, the consensus among experts was that children without symptoms should not undergo predictive testing unless immediate medical benefit would result from a positive test.

However, says physician and ethicist Lainie Friedman Ross, associate director of the MacLean Center for Clinical Medical Ethics at the University of Chicago, it’s important to distinguish between predictive genetic testing for childhood-onset conditions versus adult-onset conditions. There’s “growing tolerance” for predictive testing for childhood-onset conditions, says Ross, “as these conditions will require the parents’ input, sooner or later, in contrast with adult-onset conditions, for which the child may be able to make decisions for himself or herself in the future.”

For example, Ross notes, a predictive diagnosis of DMD in a newborn would allow parents to better plan for a condition that eventually will affect the whole family.

Some experts think there should be more flexible guidelines for predictive genetic testing of children at risk of developing adult-onset conditions. Says Ross, “There’s a growing body of literature to suggest that the ambiguity of being at risk for a disease can be just as distressing, if not more so, for a child or family than having a definite positive test result.”

Q: Can genetic testing be performed before birth?

In many cases, yes. Prenatal testing is available for many of the diseases in MDA’s program. Some parents choose to do genetic testing on an embryo before it’s inserted into the uterus, using a process called “preimplantation genetic diagnosis.” Others choose to test the fetus as it’s developing and then make a decision about whether to continue the pregnancy. Making use of prenatal testing or preimplantation genetic diagnosis is a highly personal decision. (For more on this topic, see “Do You Really Want to Know?,”  July-August 2007.)

Q: Can a DNA test tell whether I’m a carrier of a disease?

A carrier of a genetic disease is someone who doesn’t have the disease but who may transmit it to their offspring. DNA testing can detect carriers of many disorders.

Carrier testing may involve identifying a certain abnormal DNA sequence or determining if the right number of copies of a normal sequence is present.

For example, spinal muscular atrophy carrier testing depends on determining the gene copy number. Most people have two SMN1 genes, one on each chromosome 5. Having only one makes you an SMA carrier, and having none means you’ll likely develop SMA.

The SMA carrier test is “very, very accurate,” says Tom Prior, a molecular biologist at Ohio State University who developed DNA testing for SMA with MDA support in 1997. However, he says, “A limitation of SMA carrier testing is that it’s possible to have both copies of the SMN1 gene on the same chromosome. Then you get a normal result, but they’re carriers, since they are lacking an SMN1 gene on one of their chromosome 5s. We’re finding probably about 3 to 5 percent of carriers have that problem.”

Q: How can a child be born with a genetic disease if neither parent is a carrier?

In these cases, the disease was caused by a “spontaneous” (new) mutation. The mutation may have occurred very early in the child’s development in the womb or it may have occurred in a sperm or egg cell of a parent (see next question).

Q: After I gave birth to a son with Duchenne muscular dystrophy, I had a DNA test to see whether I was a carrier. They said I wasn’t, but a few years later, we had a second child with DMD. How can this be explained?

Sometimes a potentially disease-causing mutation occurs as the sperm-generating cells or egg cells are developing in a fetus who will one day be a parent. For instance, some percentage of a woman’s egg cells may contain a DMD-causing mutation, while her blood cells and other cells remain unaffected. A blood test may say she’s not a carrier, but the egg cells, from which a new baby will develop, can still be carriers. Preimplantation genetic diagnosis can detect a mutation of this type before an embryo is implanted in the uterus. (See “Can genetic testing be performed before birth?”.)

Q: How do I find out whether there’s a DNA test for my disease?

Your MDA clinic can inform you some about the availability of genetic testing for your disease. Other sources are Gene Tests, a database supported by the National Institutes of Health (go to and click on “Laboratory Directory” to search by disease, or call 206-221-4674); and Athena Diagnostics, a commercial laboratory in Worcester, Mass., that tests for many neuromuscular diseases ( or 800-394-4493, extension 2).

Q: What about genetic tests I see advertised?

Genetic testing labs that advertise on the Internet, TV and elsewhere are growing in popularity. They may ask the customer to swab the inside of a cheek or collect saliva and send the sample to the laboratory in a special mailing container, or they may advise the consumer to see a health care provider for a blood test. Some states require the involvement of a health care provider, but many do not.

Most of the tests offered this way — known as “direct-to-consumer” tests -— don’t test for neuromuscular diseases or other rare disorders. The majority address concerns that are the most common in the general population: paternity, ancestry and the presence or absence of particular genetic variants associated with common diseases.

Shawna Feeley says she’s uncertain about direct-to-consumer marketing for genetic testing. She’s cautious of labs that market this way, because she’s not always sure how valid the results are, and often there’s no one to contact for more information.

Q: What does a genetic counselor do? How can I find one?

Genetic counselors are health professionals with advanced training in medical genetics and counseling. They provide information to families to help them estimate disease risks, analyze inheritance patterns and help obtain and interpret genetic tests. They also provide supportive counseling, help with decision making, and serve as patient advocates and liaisons between families and other agencies and services.

Many MDA clinics have an associated genetic counselor, and almost all can refer you to one. You also can find a counselor through the National Society of Genetic Counselors ( or 312-321-6834).

Q: How do I pay for genetic counseling and genetic testing?

Ask whether a laboratory is CLIA-certified to do genetic testing.Some insurance plans or other third-party payers may cover genetic counseling costs. Your local MDA clinic team can guide you on genetic counseling payment options.

The full cost of testing at a commercial laboratory ranges from several hundred to several thousand dollars, depending on the test.

Insurance plans or other third-party payers may cover all or part of the cost. Some companies, such as Athena Diagnostics, have special arrangements that help make genetic testing more affordable for families. Your MDA clinic may have more information about payment options.

In addition, some research studies provide free genetic tests to participants in a study.

Q: Is there a way to know whether a laboratory is qualified to perform DNA testing? Will my doctor know how to process my sample for a DNA testing laboratory?

All U.S. laboratories that perform diagnostic testing on humans, except research labs, are regulated under the Clinical Laboratory Improvement Amendments (CLIA). Ask whether a laboratory is certified by CLIA to perform genetic tests.

Each laboratory provides doctors with specifics of obtaining and shipping a blood sample for genetic testing. Athena sends a special kit to your doctor.

Q: Are there some kinds of genetic testing that can analyze all my genes?

Recently, studies known as “whole-genome” analyses have been conducted on thousands of genes at a time to try to determine whether there are certain genetic variants that predispose people to certain conditions. These analyses are not used for disease diagnosis, but to look for “susceptibility” genetic variants related to several diseases, such as lupus, asthma, type 2 diabetes and ALS (amyotrophic lateral sclerosis). Focusing on groups rather than single individuals, these studies are so new that even experts aren’t certain how the data should be interpreted.

Q: How will I know what the results of my DNA test mean for me and other family members?

Your physician and genetic counselor can help you interpret the meaning of your genetic test results, which aren’t always straightforward.

“When they walk out of my office, I want the person to be able to look at their test results and understand what they mean,” Feely says.

DNA test reveals MD for a teen — and his seemingly unaffected brother

When Jason Adamo of Port Charlotte, Fla., was 12 years old, he developed an odd habit of walking on his toes. His mother, Katherine, an intensive-care nurse, wasn’t overly concerned, but she sought the advice of a pediatric orthopedic surgeon, who suggested that Jason’s heel cords were too short. At 13, Jason underwent surgery to lengthen them.

“At that point in time,” Katherine recalls, “we also noticed that he couldn’t fully extend his elbows. I mentioned, is that common? Is there a correlation with the legs?” The surgeon didn’t think so.

Jason wore casts on his legs for a month, after which he seemed to be walking better. Life returned to normal until one night in March 2004, when Jason was 15.

“Jason was complaining of belly pain,” Katherine recalls, “and we thought it might be appendicitis, because he had complained of it for a couple of days, and it started moving to the right.”

At the emergency room, an electrocardiogram (ECG) yielded some surprising results: The atria (upper chambers) of Jason’s heart were beating so fast they appeared to be fluttering, while the ventricles (lower chambers) showed a rate of only 45 beats a minute. Normally, the atria and ventricles are synchronized, and a normal heart rate is 60 to 100 beats a minute.

Katherine started thinking about her family’s medical history. “My father had died in his mid-30s. He had a massive stroke when he was 24 and had several strokes after that,” she says. For the first time, she began to wonder whether there was some connection between her father’s medical problems and Jason’s.

Jason was fitted with a monitor that gave continuous ECG information day and night. During the monitoring, his atrial heart rate went as high as 380 beats a minute, while his ventricular rate ranged from 120 down to the 30s.

Then a physician friend of the Adamos gave them an important clue. “He said, ‘I don’t want to scare you, but there are some forms of muscular dystrophy that present like this,’” Katherine recalls. “He was the very first one who planted that little seed there.”

A referral to pediatric neurologist Raymond Fernandez, who directs the MDA clinic at St. Joseph’s Children’s Hospital in Tampa, finally led to some answers.

Genetic testing led to an explanation for Jason Adamo’s cardiac and orthopedic problems and to an unexpected diagnosis for his brother Matthew. Back row, from left: Brothers Jason, Matthew and Christopher Adamo. Front row: Louis and Katherine Adamo, parents.“Once Dr. Fernandez looked at Jason, he sat down and said, ‘OK, this is what I think we’re dealing with,’” says Katherine. Fernandez suspected Jason might have Emery-Dreifuss muscular dystrophy (EDMD), in which contractures of the arms and legs and cardiac rhythm abnormalities often predominate.

Before any further invasive procedures were done, he suggested DNA testing, which revealed Jason had the X-chromosome form of EDMD.

Testing of Jason’s older brother, Matthew, who had no disease symptoms at all, showed he had the same EDMD-causing genetic mutation.

Now 20, Jason is doing well with a pacemaker, medications and frequent cardiac monitoring. Matthew, now 23, so far has shown no EDMD symptoms, but his heart is checked every two years. Another son tested negative for the disease, but Katherine, who is a carrier, also has been getting regular checkups.

Jason’s doctors might have come to the correct diagnosis eventually without a DNA test, although it might have taken a while. But Katherine doubts anyone would have suspected Matthew also could develop the disease. “Kind of a scary thought, isn’t it?” she says.

Preferring not to know is Kansas family’s choice

“For doctors, we’re not real scientifically based,” says Scott Eveloff, father of Andrew, now 16, who has an unclassified form of congenital muscular dystrophy and hasn’t had DNA testing.

Scott Eveloff and his wife, Ruth Eisen, live in the Kansas City area and are both physicians. They say their main goal is to give Andrew as normal a life as possible and not think too much about the future.

Scott says the family isn’t interested in learning whether Andrew has a type of congenital muscular dystrophy that causes long-term cognitive effects. “To have that hanging over us would be unacceptable,” he says. “We’ll deal with it if it presents itself.”

Andrew, he says, is fine with not having a specific diagnosis. “He desperately wants a normal life, and he doesn’t want to be reminded of his disease, or any disease. He can put up with wheelchairs and braces and physical therapy, but if he never had to see another doctor again or hear the word ‘diagnosis’ again, he’d be happy.”

On the other hand, Scott says, “If he spoke to me one day and said, ‘I need to know what’s out there for me,’ we would help him.’”

In the meantime, Andrew’s days are filled with regular high school classes, tutoring, physical therapy and water therapy. In his scant spare time, Scott says, Andrew likes to watch movies, tell jokes and read horror and mystery stories.

“Our main goal and Andrew’s main goal is to make him as normal as possible. It really occupies all of our time,” Scott says.Andrew Eveloff, 16, doesn’t know exactly what type of muscular dystrophy he has, and neither he nor his parents are seeking a diagnosis unless it would lead to treatment.

Originally, the Eveloffs were told Andrew most likely had type 1 spinal muscular atrophy, which is nearly always fatal in early childhood. “That hasn’t come to pass, so we accept the limitations of science,” Scott says. “And we also accept that, at least with us, sometimes you can get so wrapped up in numbers and pictures and cells and diagnoses that you can lose track of the fact that a kid should be just a kid.

“We rely on our neurologist to tell us if there’s some replacement therapy for a specific missing enzyme or something. I don’t go looking for it. I don’t scan the Internet. This may sound selfish, but right now there is nothing that gets to the root cause of congenital MD that a test is going to help us with. We will spare no expense if we can see a direct impact on his well-being.”

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