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Tue, Mar 19 8:00am · Not the end of the road: Delivering the diagnosis of sex-chromosome trisomy

Even if you’ve never heard the word “trisomy,” you probably know someone with the condition. March is Trisomy Awareness Month, a time to raise awareness about trisomy conditions and the challenges they can pose to individuals and families.

Trisomy means having three copies of a chromosome instead of two. Down syndrome, or trisomy 21, is the best-known trisomy. Certain less-known types occur for other chromosomes, including the sex chromosomes. The traits, or phenotypes, associated with sex-chromosome trisomy vary widely among individuals—which poses significant challenges for discussions between health care providers and families. Research supported by Mayo Clinic’s Center for Individualized Medicine (CIM) highlights how providers might better deliver the diagnosis of sex chromosome trisomy.

Megan Allyse, Ph.D.

“It’s much easier to give prospective parents a clear vision of what life would be like for a child with Down syndrome because it’s well documented, and the perspective is very positive,” says Megan A. Allyse, Ph.D., a researcher in the CIM Bioethics Program who co-authored the study. “Whereas we can’t necessarily give a clear picture for a child with sex chromosome trisomy. The child may be indistinguishable from most other children, or may struggle with social and educational factors. The uncertainty is frustrating for both parents and counselors.”

Trisomy is usually caused by a genetic mutation. Most people have either XY or XX sex chromosomes. Individuals with sex-chromosome trisomy can have XXX (known as trisomy X), XXY (Klinefelter syndrome) or XYY (Jacob’s syndrome). Often sex chromosome trisomy isn’t diagnosed until adolescence or even adulthood. Increasingly, however, the diagnosis is made before birth, as parents opt for early prenatal screening to determine whether they’re having a boy or girl. The new genetic testing that provides that answer can also detect evidence of extra X or Y chromosomes.

“The parents aren’t thinking about screening for an X- or Y-chromosome trisomy,” Dr. Allyse says. “But genetic testing can indicate a high risk of sex chromosome trisomy, which additional diagnostic tests might confirm. Most parents going into this process of prenatal genetic screening aren’t expecting that outcome. We find that their minds generally go to the worst possible scenario.”

Kirsten Riggan

That anxiety might be fueled by misinformation. Studies conducted decades ago of individuals in institutional settings found many examples of sex chromosome anomalies. “Conclusions were made that if your child has a diagnosis of XYY, he’s more likely to become a criminal. But broader population studies have found that this is absolutely not true,” says Kirsten Riggan, a research coordinator in Mayo Clinic’s Biomedical Ethics Research Program who also co-authored the CIM study.

Parents and individuals surveyed for the CIM study expressed almost unanimous interest in more optimistic portrayals of their condition from their providers, even when the outlook is uncertain. The study participants—who were recruited nationwide with help from the Association for X and Y Variations (AXYS), a patient-advocacy group—also noted a need for greater coordination of their children’s medical care and direction in accessing follow-up care and support.

“What families want to hear is that this diagnosis is something we know about, other people have had this experience, and we can help you get through this,” Dr. Allyse says. “Lots of children live with this condition. It may mean some adjustments. But it’s not by any stretch of the imagination the end of the road.”

Wide variation in traits

It’s difficult to generalize about the traits of sex chromosome trisomy. Many individuals have mild symptoms, but some have significant health problems needing specialty care.

Females with trisomy X tend to be tall but often have no physically distinguishable characteristics. Symptoms may be mild, usually involving minor motor development and language delays. Sex development and fertility are frequently normal. “Typically, the phenotype isn’t as noticeable with trisomy X,” Ms. Riggan says.

Similarly, individuals with XXY or XYY may be taller than average. They may have a predisposition for weight gain that can lead to diabetes, and experience delays in development and learning. But not all do.

“There are plenty of men who grow up, graduate from college, get married and find out they have Klinefelter syndrome only when they try to have children,” Dr. Allyse says. Men with Klinefelter syndrome generally have impaired fertility, although Mayo Clinic has experience helping men with the condition to father children through in vitro fertilization. Men with Jacob’s syndrome generally have normal sexual development and fertility.

The biggest challenge is a correlation in males between sex chromosome trisomy and impaired executive function, or the thinking processes that control behavior. “Sometimes these boys have a misdiagnosis of attention deficit/hyperactivity disorder, antisocial behavior or autism,” Dr. Allyse says. “The finding of a genetic trisomy—which we often see when boys are ages 10 to 15—comes as a huge relief to the family because they finally have an underlying cause for the behavior, and can get support.

“We need more education among non-genetic health providers about the phenotypic signs of sex chromosome trisomy, so children can be diagnosed earlier,” she adds. “What we hear from these families is, ‘I just wish somebody had told us when we got the diagnosis that it was possible for us to have a great life.’ ”




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Thu, Feb 14 8:00am · When the shoelaces fray: short telomere syndromes

Unlike gray hair, one of the most significant signs of aging is invisible to the naked eye. Deep inside cells, at the tips of thread-like chromosomes, structures known as telomeres protect chromosomes from deterioration—a bit like the way caps at the ends of shoelaces prevent fraying. Telomeres naturally shorten as people age.

But sometimes, an inherited gene mutation causes telomeres to shorten at a faster rate. Abnormal telomere shortening results in accelerated-aging syndromes that affect many parts of the body and can occur in children or adults. The severity of short telomere syndromes varies, but they increase cancer risk and can lead to organ failure and death.

With help from the Center for Individualized Medicine, Mayo Clinic uses a precision-medicine approach to manage short telomere syndromes. Mayo’s Premyeloid & Bone Failure Disorder Clinic provides diagnostic testing, multidisciplinary treatment and genetic counseling for short telomere syndromes.

Mrinal Patnaik, M.B.B.S.

“Short telomere syndromes have been recognized for several decades. But diagnosis has been very difficult because it requires highly specialized testing. With the advent of precision genomics, we have the opportunity to identify and manage these disorders, for the benefit of patients,” says Mrinal Patnaik, M.B.B.S., a hematologist who directs the premyeloid disorder clinic.

Although short telomere syndromes are considered rare, Mayo Clinic sees five to seven people with the disorders a month. “We think short telomeres are much more common than has been reported, and anticipate that these new precision-medicine tools will bring a fair number of cases to light,” Dr. Patnaik says.

‘The mysterious telomere’

The 2009 Nobel Prize in medicine was awarded for discoveries about what the Nobel committee called “the mysterious telomere.” Short telomeres affect parts of the body where stem cells actively divide, including bone marrow, skin and the tissues lining the lungs and digestive tract.

“These stem cells rely on telomeres to keep their integrity. Short telomeres cause the stem cells to prematurely die,” Dr. Patnaik says.

Short telomeres can lead to scarring in the lungs and liver, narrowing of the digestive tract, bone marrow failure and immune-system deficiency. The severity of the inherited condition increases with each generation—a phenomenon known as genetic anticipation.

“Children inherit from their parents not only the genetic mutation causing short telomere syndrome but also shorter and shorter telomeres,” Dr. Patnaik says. “As a result, the syndromes tend to occur at a younger age and with more severe manifestations in each generation. Eventually the life span is highly limited.”

Initial diagnosis is a challenge because the signs and systems of short telomere syndromes are diverse. “There is a lack of awareness,” Dr. Patnaik says. “A person with lung fibrosis and failing bone marrow might see a lung specialist or a blood specialist who isn’t familiar with these multispecialty syndromes and doesn’t put the clues together.”

Mayo Clinic looks for certain signs and symptoms with unexplained causes, including:

  • Personal or family history of premature graying of hair
  • Low red blood cell, white blood cell or platelet counts
  • Thickened, stiff or scarred lung or liver tissue

If short telomere syndrome is suspected, Mayo Clinic can arrange for sophisticated testing that measures the length of telomeres in an individual’s blood cells. Once short telomeres are identified, Mayo Clinic has a genetic sequencing panel to help find the mutation causing short telomeres. If genetic sequencing doesn’t uncover a mutation, whole exome sequencing—which looks at all disease-causing genes in an individual’s DNA blueprint—can be performed.

Certain genetic mutations are known to be associated with short telomeres. But only 40 to 50 percent of people with short telomeres have one of these known mutations.

“The fact that more than half our patients with short telomeres do not have detectable gene mutations on sequencing panels indicates that we haven’t yet discovered all the mutations that affect telomere length,” Dr. Patnaik says. “There also may be nongenetic mechanisms involved—which is a Pandora’s box we haven’t even opened yet.”

Seeking new treatment options

Recent research indicates that treatment with danazol, an anabolic steroid, may slow the rate of telomere shortening, as well as improve blood counts and stabilize lung and liver disease in people with short telomeres. Laboratory experiments with gene therapies are also underway. Mayo Clinic is involved in research efforts in both these areas.

“Unfortunately, while we increasingly understand the genetics and consequences of short telomeres, much work remains to be done with regards to effective treatment modalities,” Dr. Patnaik says.

Transplantation can be an option for people who experience organ failure. However, individuals with short telomere syndrome often need multiorgan transplants: bone marrow transplantation as well as a liver or lung transplant, which makes the process extremely challenging.

“The vast majority of people with short telomere syndrome are turned down for transplant because not many centers are equipped to perform multiorgan transplantation,” Dr. Patnaik says. “Our precision genomics clinic is working with the various transplant groups within Mayo Clinic to pursue safe multiorgan transplantation for these patients. At Mayo Clinic, we have a great opportunity to use precision medicine to benefit people with short telomere syndromes.”



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Mon, Jan 21 11:12am · Test offers hope for people with severe kidney disease

Optimal treatment requires knowing what caused a medical condition. If your arm is broken because you fell, a simple cast might be enough. But if a tumor in your bone made it brittle, you need very different treatment.

For people with a rare kidney condition—known as focal segmental glomerulosclerosis (FSGS)—identifying the cause is critical. Patients with an FSGS lesion identified through kidney biopsy have abnormal amounts of protein in their urine. As a result, over time the kidney’s filtering units become scarred, leading to permanent kidney damage and even kidney failure.

There are three main types of FSGS—primary, secondary and genetic—and each requires a different treatment approach. The wrong approach can lead to inappropriate and perhaps harmful therapy.

A pilot study funded by Mayo Clinic’s Center for Individualized Medicine has found a higher-than-expected proportion of people with FSGS have a genetic cause for the disease. Pinpointing a genetic cause paves the way to individualized treatment that can eliminate unnecessary drugs and make kidney transplantation more successful.

Fernando Fervenza, M.D., Ph.D.

“Until recently, a genetic variation contributing to the disease was found in only about 10 percent of FSGS patients lacking a clinically identifiable cause. In our pilot study, we found a potential genetic explanation in about 50 percent of cases,” says Fernando Fervenza, M.D., Ph.D., director of Mayo’s Nephrology Collaborative Group. “These are very exciting results. We believe genetic causes of FSGS are much more common than we once thought. Physicians have just not been looking for the exact cause of these renal diseases with the right technology.”

Mayo Clinic researchers used a testing panel that involves 50 genes known to cause FSGS. Patients who tested positive were given a diagnosis of genetic FSGS. Patients who tested negative were given whole exome sequencing, which looks for all genes in an individual’s DNA blueprint, hoping to discover new genes causing the genetic type of FSGS.

In primary FSGS, the increase in urinary protein is due to the presence of a circulating factor or factors that are toxic to the kidney’s filtering units. The origin or type of these factors is unknown. In secondary FSGS, scarring occurs when a kidney is forced to overwork for some reason, such as obesity, loss of one kidney or low birthweight that may result in abnormally small kidneys. Certain drugs and viral infections can also cause FSGS.

Ladan Zand, M.D.

“Unlike people with secondary FSGS, patients with the genetic FSGS generally don’t have an obviously identifiable cause that explains the presence of protein in their urine,” says Ladan Zand, M.D., a nephrologist in Mayo’s Nephrology Collaborative Group who worked on the pilot study.

In the past, the lack of easily accessible genetic testing may have contributed to genetic causes being overlooked. As a result, many patients have often been misdiagnosed as having primary FSGS—and been prescribed steroids or other immunosuppressive treatments commonly used for primary FSGS.

“Of course, these patients didn’t respond to steroid or other forms of immunosuppressive treatment because their disease was genetic,” Dr. Fervenza says. “Treatment with high-dose steroids or other forms of immunosuppression has significant side effects. Finding a genetic cause for FSGS can spare patients from taking these medications unnecessarily.”

Because primary FSGS frequently recurs, people with that diagnosis sometimes aren’t eligible for kidney transplant. “But transplant centers are more willing to take patients whose FSGS is due to a genetic mutation. The donor kidney will lack the genetic mutation, so the disease would not recur,” Dr. Fervenza says.

The results of Mayo Clinic’s pilot study indicate that genetic testing might be usefully performed in any adult who has what appears to be a primary FSGS lesion—but who doesn’t respond to immunosuppressive therapy. “We believe the results of this research will significantly inform clinical practice and change the standard of care for patients with FSGS,” Dr. Fervenza says.


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Dec 10, 2018 · RIGHT 10K: Blazing a trail to health care's future

Mayo Clinic’s Center for Individualized Medicine (CIM) is nearing the finish line of the first stage of its unique RIGHT 10K study—an effort that doesn’t involve running shoes but nevertheless is paving the way to prescribing medications matched to a person’s genetic code.

RIGHT 10K is a clinical research project to genetically sequence more than10,000 individuals and place the results in those individuals’ electronic health records (EHRs). That information is critical because genetic differences can affect how a person processes and responds to medications. The right drug matched to a person’s genetic makeup could maximize the drug’s therapeutic benefit. However, the wrong drug or dosage can make a medication ineffective or even fatal.

Loading this “pharmacogenomic” information into EHRs is a huge challenge. Mayo’s early adoption of this strategy and comprehensive approach can guide providers as pharmacogenomics reshapes medical care.

Jessica Wright, Pharm.D. R.Ph.

“We’re now able to tell if patients could be at increased risk of therapeutic drug failure or devastating side effects. It’s critical to get that information preemptively into EHRs so that providers can be reliably notified of any adverse drug-gene interaction at the point of care,” says Jessica A. Wright, Pharm.D., R.Ph., a Mayo Clinic pharmacist specializing in pharmacogenomics.

Launched in 2016 in collaboration with Baylor College of Medicine and OneOme, a company that Mayo co-founded, RIGHT 10K will have entered data from all 10,000-plus patients into the EHR by the end of 2018. A OneOme interpretive report for 76 pharmacogenes are included in the data. Thirteen of those pharmacogenes can trigger an onscreen alert, if a physician inputs a prescription that might be ineffective or harmful for a particular patient based on their genes. The physician can then prescribe a different medication or adjust the dose.

The number of patients and pharmacogenes makes RIGHT 10K the most comprehensive effort to date to place pharmacogenomic information in individuals’ medical records. RIGHT 10K will systematically evaluate the impact of these clinical-decision alerts to determine if they improve prescribing decisions and ultimately health care. The lessons learned by Mayo Clinic can guide providers in the pharmacogenomics era.

Eric Matey, Pharm.D., R.Ph.

“Through RIGHT 10K we are training multiple healthcare providers at Mayo Clinic about pharmacogenomics. There is an opportunity for us to provide assistance and educate pharmacists elsewhere,” says Eric T. Matey, Pharm.D., R.Ph., a Mayo Clinic pharmacist specializing in pharmacogenomics.

Meeting the technical challenges

Complex pharmacogenomics information must be easily accessible for busy clinicians. “Having an effective computerized system is essential because it’s quite overwhelming for patients and their providers to remember pharmacogenomic testing results,” Dr. Wright says. “Pharmacogenomic information is stored in the EHR in ways that can enable alerts to clinicians and provide links to guidance when most needed.”

Another challenge is avoiding the overuse of alerts, which can interrupt workflow in busy clinics and possibly cause providers to ignore the popups. “Rather than bombarding providers, we limit the number of alerts they really need to pay attention to, in order to avoid harm to patients,” Dr. Matey says.

Mayo Clinic is also committed to designing EHRs that can easily incorporate new information —on a newly discovered pharmacogene, for example. A person’s genome doesn’t change; but our understanding of pharmacogenes improves as research advances. “Updating information in the electronic health records is a challenge we’re working on,” Dr. Wright says.

Although pharmacogenomics information will increasingly be considered an essential part of a patient’s medical record, EHRs will never replace clinicians.

“Pharmacogenomic results must not preclude clinical judgment. If a patient is doing well on a certain medication, but the pharmacogenomics test results are stating otherwise, the clinician should go ahead and use clinical judgment and continue the medication,” Dr. Matey says. “However, to avoid harm, we must work to give providers the information they need to make these clinical judgments.”



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