Like so many momentous events in the lives of young women, this one began with a missed period. Julia* had been on oral contraceptives for years, but when she went off the pill, her period did not start up again. Her doctor told her this was not unusual, but months later she still was not menstruating and had begun to experience hot flashes. Hormone levels showed she had a condition called primary ovarian insufficiency—in other words, premature menopause. She was 22 years old.

Julia's primary doctor referred her to a specialist in reproductive endocrinology, who told Julia there was only a 2 percent chance she would ever have children. “It was such a heartbreaking shock for me,” she says. “I overcompensated by feeling I had to be perfect, look perfect, be a perfect woman because a core part of my femininity had been taken away.” She was still single and imagined that men would not want to have anything to do with a woman who could not have children.

Meanwhile Julia had begun to notice that something was off with her father, David. In his early 60s and recently retired, David had always been an avid fisherman whose steady hands had reliably tied flies for decades. But he had developed a tremor and was having trouble rising from a chair. His movements were growing slower. These changes were gradual and might have gone unnoticed had it not been for Julia's own startling discovery. Her endocrinologist ordered a genetic test to better evaluate her menopausal symptoms and in the process discovered an explanation for both Julia's infertility and her father's tremor: they were carriers of fragile X.

In this age of heightened autism awareness, many people have heard of fragile X syndrome as the most common known genetic cause of autism and intellectual disability. Fragile X children have a number of characteristic physical features such as an elongated face, prominent ears and low muscle tone. Many have symptoms of autism, and many struggle with severe anxiety and disturbed behavior in addition to cognitive impairment. But no one in Julia and David's family is intellectually disabled. They are instead carriers of a genetic trait known as the fragile X premutation, an alteration to the X chromosome that puts them at risk of having a child with fragile X syndrome.

Although the syndrome is rare, the premutation is surprisingly common—with a prevalence of around one in 150 women and one in 450 men in the U.S. In addition to causing infertility, the mutation can affect the brain, altering mood and behavior and in some cases causing a devastating movement disorder and dementia. Some evidence has linked it to a variety of autoimmune conditions, fibromyalgia and neuropathic pain, obstructive sleep apnea and restless legs syndrome, among others. But very few doctors are aware of the premutation, and most carriers have no idea they are affected.

That may be about to change. A small group of scientists is intent on uncovering the full consequences of the premutation. To do so, they are reversing the usual order of genetic research: rather than seeking the genetic roots of an established disease, they are using a known gene defect to characterize a new condition, by sharing information about people carrying the premutation. In the process, they are illuminating how a gene that scientists thought was silent may have been shaping the stories of countless families.

Molecular Anomaly

Suzanne is a journalist who covers women's health, but she drew a blank when her ob-gyn told her that prenatal testing showed she was a carrier of fragile X syndrome. “I said, ‘What are fragile eggs?’” she recalls. Her doctor explained that Suzanne was a fragile X premutation carrier and suggested she consider amniocentesis to evaluate her unborn child.

What exactly is a premutation? To understand that, one has to know something about the inheritance of fragile X syndrome. In 1991 researchers identified and sequenced the FMR1 gene, which codes for a protein needed for normal brain function. The FMR1 protein regulates many processes in the brain. Although its exact role is unknown, this much is clear: children who lack the protein are born with fragile X syndrome.

The FMR1 gene lies on the X chromosome. Like many genes, it contains a certain amount of noncoding DNA, so called because it does not represent any particular protein. In the case of the FMR1 gene, this consists of repeated triplets of cytosine, guanine and guanine (CGG repeats), basic components of DNA. It is normal to have these CGG repeats; most people have around 30 on their FMR1 genes.

Premutation carriers, however, have between 55 and 200 repeats, which makes the gene unstable. The “pre” in “premutation” refers to the way that CGG repeats on an unstable FMR1 gene can expand over generations. Within a generation or two the gene could be burdened with more than 200 CGG repeats, the threshold number for the full fragile X mutation. At that point, the gene stops functioning, and the FMR1 protein cannot be made. The result is fragile X syndrome, a name derived from the fragile appearance of the X chromosome, which looks as if a piece were about to fall off.

Because this is an X-linked mutation, its prevalence in men and women differs. Girls have two X chromosomes—one each from their mother and father—so they usually have a healthy X to balance out the defective one. Boys have only one X chromosome, which they inherit from their mother. As in other X-linked conditions, such as hemophilia and color blindness, fragile X syndrome is therefore much more pronounced in boys, and girls are more likely to be carriers.

In 1943, when British physicians first described what came to be known as fragile X syndrome, geneticists believed that carriers had only one thing to worry about: the possibility of having a developmentally disabled child. But now we know otherwise. In the late 1990s a behavioral pediatrician, Randi Hagerman, working in concert with geneticists—including her husband, Paul Hagerman, their colleague, biochemist Flora Tassone, and a genetic counselor, Louise Gane—described a new syndrome associated with fragile X. The research team, all of whom (excepting Gane, who recently retired) are now associated with the MIND Institute at the University of California, Davis, studied and treated fragile X kids. Randi Hagerman and Gane followed fragile X children from diagnosis to adulthood and developed close relationships with the mothers of their patients.

They noticed that many of these women had concerns about their own fathers. These grandfathers of kids with fragile X syndrome had begun to develop tremor, trouble walking and even personality changes. At an event for fragile X families in 2000, Hagerman and Gane asked mothers to raise their hands if they thought their fathers were impaired. The researchers were stunned when a third of the audience raised hands.

They began to study the grandfathers of their fragile X patients and to characterize what they dubbed fragile X–associated tremor/ataxia syndrome (FXTAS). Claudia Greco, a MIND Institute neuropathologist, discovered the underlying cause when she was able to obtain four grandfathers' brains at autopsy. It turns out that the premutation is not just a “lite” version of the full mutation but has a completely different mechanism. Because the premutation carrier has extra CGG repeats, he or she makes an abnormal amount of associated RNA—the molecule that directs the synthesis of proteins from DNA. The excess RNA binds necessary proteins, which pile up “like a scrum in rugby,” as Paul Hagerman describes it. These “scrums” of RNA and protein are called inclusion bodies, and the FXTAS brains that Greco studied were full of them. The toxic clumps lead to tremor and ataxia in late midlife and to more severe symptoms later on.

In 2010 Tassone and Elizabeth Berry-Kravis, a neurologist at Rush University in Chicago, further described the brain differences in FXTAS patients. Among the most notable are changes in white matter, detectable by MRI, in the middle cerebellar peduncles (MCPs), structures that connect the brain's hub for motor control, the cerebellum, to the upper brain stem. This signature is highly specific to FXTAS and is now a diagnostic criterion. Randi Hagerman notes that it was not until this so-called MCP sign was established that the medical community embraced FXTAS as a real entity.

Damage to the cerebellum and frontal lobes also helps to explain the behavioral changes seen in individuals with FXTAS. James Bourgeois, a psychiatrist at the University of California, San Francisco, describes the personality change associated with FXTAS as one of “executive dysfunction.” Coordination between the cerebellum and the frontal lobes is essential for planning and organizing behavior, as well as maintaining attention and focus long enough to carry out a planned behavior. Put simply, the cerebellum organizes movements, and the frontal lobes keep the activity on track by strengthening impulse control, thereby inhibiting deviations from the plan.

Julia's father, David, has early signs of FXTAS, which is causing his tremor, a swaying gait and tendency to fall. He feels “tippy” when he gets up too fast, and a couple of years ago, he broke his wrist falling down stairs. Of more concern is his emotional reactivity. He describes his emotions as “amplified by 10 percent.” In particular, he gets angry: “Sometimes the rage is more than I've ever experienced.” David was always passionately engaged in creative work as an artist and teacher, but in the past year or two he has let it drop. He does not find that disturbing—calling it just a new phase of life—but his friends and family do. What seems to his friends to be a crucial part of his identity is no longer that important to him.

A New Disease

In 2015 at the Second International Conference on the FMR1 Premutation, 80 researchers and clinicians from all over the world came together in Sitges, Spain, to discuss the phenotype of the premutation—not the carrier's genes, but how they manifest in the individual. This tiny group of researchers is engaged in fully describing the symptoms and behaviors of people who carry the premutation. As they share findings, they are, in a sense, defining a new disease.

FXTAS is just one part of this condition. Another component is infertility: 20 percent of female premutation carriers, like Julia, will develop primary ovarian insufficiency by the time they are 40 years old. A long list of other medical issues recur in the community of carriers. By gathering more and more data from carriers, the scientists hope to sift through whether and how these conditions relate to the premutation.

Evidence presented at the conference suggests that the premutation may affect mood, anxiety and personality, in both male and female carriers. But such links can be difficult to untangle. For example, many parents of fragile X kids suffer from depressed mood and anxiety, and some have true anxiety disorders such as phobias and obsessive-compulsive disorder. Historically the presence of depression and other psychiatric conditions has been attributed to the stress of raising a child with fragile X syndrome. As early childhood expert Don Bailey of the nonprofit Research Triangle Institute pointed out at the conference, the most difficult challenge faced by premutation carriers is management of their children's disruptive or autistic behaviors. Most mothers attributed their anxiety to chronic stress.

Yet psychiatrists and behavioral pediatricians who work with mothers of fragile X children wondered if something else was going on. All mothers of fragile X children are themselves premutation carriers, which leaves open the possibility that some of the psychological patterns in this group reflect genetics. Support for the latter idea came from findings in childless sisters of fragile X mothers—premutation carriers who were not raising fragile X kids—who also had a higher than average incidence of depression and anxiety. Furthermore, the mothers of children with autism not caused by fragile X syndrome, who therefore faced similar parenting challenges but did not carry the premutation, were found to have a lower incidence of mental disorders than fragile X moms.

As genetic testing became more sophisticated, researchers were able to show that the presence and severity of psychiatric symptoms was related to the number of CGG repeats. In a study published in 2015 Danuta Loesch, a neurologist and geneticist at La Trobe University in Australia, and her colleagues studied a sample of 299 adult female carriers and found that those women with midrange expansions—60 to 80 repeats—were more symptomatic than those with larger or smaller numbers of repeats.

Further, in a 2012 study a team of researchers, including Marsha Mailick of the University of Wisconsin–Madison, looked at the biological response to stress in 82 mothers of children with fragile X syndrome. Mothers with midsize repeats produced more of the stress hormone cortisol when confronted with stressful life events. Why women with midrange expansions have a bigger stress response than those with more CGG repeats is a counterintuitive finding that remains unexplained.

Beyond parents of kids with fragile X syndrome, the psychological changes associated with the premutation are most clearly established in FXTAS. These patients primarily show problems with behavior, which may be vulgar or socially inappropriate (in contrast to Alzheimer's dementia, for example, which can involve behavioral changes but is primarily characterized by memory deficits). Some, like David, may become emotionally labile or lose interest in formerly loved pursuits. Psychiatrist James Bourgeois notes that most of the time, psychiatric symptoms precede tremor and ataxia in patients with FXTAS, and dementia follows the onset of the movement disorder. Even among carriers who never develop the worst-case scenario of FXTAS, he has observed anecdotally that many premutation carriers have “an avoidant, deferential character style” and may be drawn toward isolated pursuits.

Randi Hagerman, the world's foremost authority on the premutation, sees patients who travel from all over to consult her team at U.C. Davis's MIND Institute. Thus self-selected, they tend to be educated and competent—doctors, lawyers, rabbis and more than one jet pilot. Even so, Hagerman notes that many patients, especially women, have told her they need to work really hard to maintain eye contact. At the conference, Molly Losh, a psychologist at Northwestern University, spoke of premutation carriers' greater tendency than noncarriers to perceive standardized faces as “untrustworthy.” Jane Roberts, a psychologist at the University of South Carolina, presented unpublished evidence that even infants with the premutation had mild autistic features. These may represent the avoidant phenotype described by Bourgeois.

On the other hand, David Hessl, a psychologist at the MIND Institute, cautioned that people need to know that many premutation carriers have no symptoms at all. About 40 percent of male carriers will develop FXTAS, with varying degrees of severity, sometime between their 50s and their 80s, as will a small percentage of females. Carriers without FXTAS, Hessl believes, may have a higher risk of psychiatric disorders, but it is probably not much higher, and it is only a risk, not a given.

Scientists say they are limited by the fact that they do not have enough patients to study—a recurring theme at the conference in Spain. There was a sense of urgency about the need to share tissue samples and data. Maureen Leehey, a FXTAS neurologist at the University of Colorado School of Medicine, estimated that there are as few as 500 known FXTAS patients in the U.S. Yet according to the Centers for Disease Control and Prevention, 320,000 U.S. males are premutation carriers, and of these more than 100,000 are likely to develop FXTAS during their lifetime. The problem is that most people do not know they are carriers.

Genetics Revolution

For-profit genetic-testing laboratories can now screen women for more than 100 genetic conditions, including the fragile X premutation, with a saliva sample patients can mail from home. Such testing programs may lead to the identification of thousands of premutation carriers in the next few years. The profits go to genetic-testing companies, but it is a potential gold mine for subject-starved researchers as well. Meanwhile patients who test positive for the premutation will want to know what to do about it.

For women who learn of their carrier status during pregnancy, as was the case for Suzanne, prenatal testing such as amniocentesis can reveal whether or not the fetus is affected. In Suzanne's case, it showed that her baby carried the premutation, not the full mutation. Today Ruby is a healthy eight-year-old. When she is old enough, Suzanne will let her know about the risks conferred by the premutation, and when she is of reproductive age, she will have her own choices to make.

Virginia, who has almost 200 repeats, is a recently married 28-year-old carrier who designs software. Her younger brother and sister both have the full fragile X syndrome, and she has always known and embraced the fact that someday she would be responsible for their care. “Having grown up watching my parents struggle, it's not something I would take on, knowing it could be avoided in a way I feel comfortable with,” she says. Before the wedding, she and her husband-to-be talked frankly about adoption, abortion and other possibilities.

Virginia does not have ovarian failure, but with nearly 200 repeats, her chance of bearing a child with fragile X syndrome is close to 100 percent if the fetus inherits the mutated X. Fortunately, there is a 50 percent chance the baby will inherit her normal X chromosome. If Virginia decides to start a family, she has a handful of choices: not having her own children, using a donated egg, having early chromosomal analysis followed by termination if the fetus has the full mutation, and in vitro fertilization with preimplantation diagnosis. In that procedure, eggs are harvested and fertilized in the lab; then the embryos are evaluated for the presence of the fragile X chromosome and only the healthy ones implanted.

Virginia considers the necessity for premarital family planning a great opportunity, a reckoning that all young couples could benefit from. She is nothing like the anxious, deferential type described by Bourgeois, and she gets her spunk from her premutation-carrier mother. “My mom's badass,” Virginia says. She adds that if her husband did not want to be with someone who was open about fragile X syndrome, the premutation and pregnancy, “he should have married somebody else.”

The question of who should be screened, and when, is an active area of research in the fragile X community. Virginia and her husband have surely benefited from their knowledge of her family history. Yet the American Congress of Obstetricians and Gynecologists does not currently endorse universal testing for fragile X syndrome. Universal screening of newborns for fragile X has been proposed but is controversial. The MIND Institute's Flora Tassone reviewed the risks and benefits of newborn screening in 2014, noting that such screening would identify premutation carriers, who would then require further evaluation and treatment by an infrastructure that does not yet exist. There is currently no approved treatment for FXTAS. On the other hand, premutation carriers could benefit by making lifestyle changes to protect their health, such as avoiding nicotine and other toxic substances, treating high blood pressure and other conditions that can damage the brain, and seeking treatment for depression and anxiety.

Research on the fragile X premutation is challenging some of geneticists' most basic assumptions. As University of California, San Diego, sociologist Daniel Navon explains, our understanding of the fragile X premutation has changed from its being seen as simply a “carrier” gene, to a gene that confers a high risk of two adult-onset conditions, and now to a common, generally mild genetic condition that manifests from infancy. “I know a lot of geneticists are starting to question the very notion of carrier genes, and the fragile X premutation could be a vanguard case for this kind of revolution,” Navon says. If seemingly unaffected carriers of other genetic diseases turn out to be mildly affected in ways that have not yet been noticed, then genetic disorders are more common than we ever suspected.

Today, five years after her diagnosis, Julia has more on her mind than the premutation. She is prone to introspection; some experts might say this is part of the premutation carrier phenotype. Cognitive-behavioral therapy has helped her manage her anxiety and restore her healthy self-esteem. She has gone back to school to pursue a long-held dream and says she has made peace with her condition: “It's part of who I am, but it doesn't define who I am.” Sometimes she shares in the family worry about what may lie ahead for herself and her father, but for now, she says, “I'd rather focus on the present.”