Gene defect for fragile X more widespread

UC DAVIS (US) — The first large-scale effort in the US to screen newborns for the genetic defect that can result in fragile X syndrome finds it occurs more frequently that previously thought.

The defect on the X chromosome can result in a wide array of conditions—from learning and emotional difficulties to primary ovarian insufficiency in women and tremors in middle-aged men.

Researchers screened more than 14,200 male and female infants using a new test developed at the University of California, Davis. The test was conducted using blood spots obtained from infant heel pricks as part of the normal newborn genetic screening process.

The team reported findings in the journal Genome Medicine.

The investigators examined the prevalence of expanded alleles of the fragile X mental retardation 1 (FMR1) gene. Defects in FMR1 cause conditions as diverse as fragile X syndrome—the leading cause of intellectual disability and the leading known single-gene cause of autism—and a Parkinson’s disease-like condition called fragile X-associated tremor/ataxia syndrome, or FXTAS.

The term “fragile X” is used because of the altered appearance of the X chromosome among sufferers from the conditions.

“This study demonstrates that there is a higher frequency of mutations of the FMR1 gene across racial and ethnic groups than previously believed,” says Randi Hagerman, medical director of the UC Davis MIND institute and the study’s senior author.

1 in 400 boys

The degree of disability from defects in FMR1 depends upon the number of repetitions of the sequence of the proteins cytosine-guanine-guanine (CGG) in the promoter region of the gene.

The range of repeats in normal individuals is between six and 40. CGG repeats greater than 200 cause what is called the full mutation and fragile X syndrome. Fewer repeats—in the range of 55 to 200—result in a variation called a premutation.


The current study found the estimated prevalence of the premutation to be 1 in 200 females, a finding somewhat greater than earlier estimates. However, it estimates the prevalence among males to be 1 in 400—double what had previously been reported. The researchers said that the sample size in the current study was not great enough to estimate the true prevalence of the full fragile X mutation, currently estimated at between 1 in 2,500 and 1 in 8,000 females and 1 in 5,000 males.

While most people with the premutation appear normal, some individuals can have mild difficulties in childhood, such as learning problems or emotional difficulties, including social anxiety and attention-deficit/hyperactivity disorder (ADHD), says Hagerman.

Individuals with the premutation also can suffer from FXTAS, which causes debilitating tremors, balance problems and dementia, primarily in older men, and premature ovarian insufficiency in women.

More screening?

Flora Tassone, study leader and a professor-in-residence in the biochemistry and molecular medicine department, developed the polymerase chain reaction (PCR)-based test used in the current study. A detailed description of the test was published January 2008 in the Journal of Molecular Diagnostics.

“This study shows that newborn screening for the FMR1 mutation is technically possible on a large scale,” Tassone says. “However, the screening will identify far more carrier and gray-zone infants than those with a full fragile X mutation.

“As we now know that there may be clinical involvement with these individuals, such as FXTAS, we need to better understand the impact of identifying these mutations on families before widespread newborn screening can be instituted.”

Hagerman says the study is important because early intervention can be helpful for children with the mutation who experience developmental problems. In addition, a baby who is positive for the mutation will have other family members who also carry the mutation.

Genetic counseling is essential for the family members, in addition to treatment for the medical or psychiatric problems associated with the premutation or full mutation, she adds.

Individuals interested in obtaining further information about or participating in fragile X-related research may contact Louise Gane at, 916-703-0238.

The Eunice Kennedy Shriver National Institute for Child Health and Human Development, American Recovery and Reinvestment Act, and the US National Center for Advancing Translational Sciences supported the study. Researchers from UC Davis, Rush University Medical Center, the University of Wisconsin, and RTI International collaborated on the study.

Source: UC Davis