Experts call for universal fragile X screening

Transcription

1 NEWS Experts call for universal fragile X screening BY ANDREA ANDERSON 1 APRIL / 5

2 Clean sweep: Universal screening would detect even asymptomatic carriers of fragile X. Screening for genetic precursors to fragile X syndrome, the most well established genetic risk factor for autism, should be expanded to all women who are pregnant or plan to be, some geneticists say. 2 / 5

3 Prenatal fragile X testing is generally reserved for those women who have a family history of fragile X syndrome. But a study published online on 19 March suggests that doctors should be more vigilant about screening women who could be carriers of the disease? for example, those with autism or other behavioral conditions 1. Some fragile X carriers have no obvious risk factors. "Nothing short of universal screening" would detect those carriers, says author Owen Phillips, obstetrician and medical geneticist at the University of Tennessee Health Sciences Center. "A lot of people are recommending universal screening." Fragile X syndrome is the most common inherited form of mental retardation, affecting about 1 in 4,000 males and 1 in 8,000 females. The syndrome is characterized by delayed learning and unusual facial features, including elongated heads and large, pronounced ears. A subset of those who have fragile X? between 5 and 60 percent? are also diagnosed with autism spectrum disorders. Unlike autism however, fragile X is known to be a monogenic condition: it is caused by a mutant version of a single gene on the X-chromosome called FMR1. Three bases in a regulatory region of the FMR1 gene are repeated as many as a few hundred times, altering or inactivating the gene. The FMR1 gene codes for a protein called fragile X mental retardation protein, believed to influence the activity of some glutamate receptors in the brain. The severity of fragile X depends on the size of the expansion in FMR1. Someone with 55 to 200 DNA sequence repeats has what's called a pre-mutation, whereas those with 200 or more are classified as having the full mutation. Better tests: At one time, fragile X testing was limited to looking for kinks in the X chromosome, but the discovery of FMR1 in the early 1990s opened the door for DNA-based tests. Molecular techniques such as PCR and Southern blot analysis can be used in tandem to detect the size of FMR1 expansions and subsequent genetic modifications. With the advent of these molecular tests, "It's like night and day," says Flora Tassone, a biochemist at the University of California Davis' MIND Institute. "Now we can really screen both genders for normal [sequence], pre- and full mutations." The tests are primarily used diagnostically? for instance, for children with unexplained mental retardation, developmental delays or autism. But they can also be used to screen asymptomatic X carriers with a family history of fragile X. "The problem is that there are not very good numbers [regarding carriers]," Tassone says. "There's not very good epidemiology." 3 / 5

4 The American College of Obstetricians and Gynecologists 2 and the American College of Medical Genetics 3 both recommend prenatal testing for fragile X if the mothers-to-be are known carriers of a fragile X mutation. But those with pre-mutations often don't have symptoms, and if they do, have different features that appear later in life. In the latest study, for example, the researchers looked at family histories for 17 children diagnosed with fragile X syndrome. What they found was surprising: though the mothers are all carriers of pre-mutations, only eight? who came from families with a history of fragile X syndrome or unexplained mental retardation? had risk factors that would definitely raise red flags. Five others had relatives with autism, speech or hearing problems, attention deficit hyperactivity disorder or other behavioral disorders. Four had no established risk factors. More carriers would be detected if testing guidelines were followed in their broadest sense, Phillips says. "If they had a very low [testing] threshold, they might have picked them up." One reason is that the tests are relatively expensive and many doctors lack the experience to interpret the results. That means trained genetic counselors may need to help families decipher the results of the test and the implications. Universal screening is also controversial because there's no cure for fragile X. Still, there are early interventions that can benefit those with fragile X syndrome. As Phillips says, "Fragile X is more common than Down Syndrome and we do extraordinary things to detect Down Syndrome." References: Rajendra K. et al. Am. J. Obstet. Gynecol. in press (2008) PubMed? American College of Obstetricians and Gynecologists Committee on Genetics Obstet. Gynecol. 107, (2006) PubMed? Sherman S. et al. Genet. Med. 7, (2005) PubMed? 4 / 5

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