Newborn screening for fragile X syndrome (FXS) is feasible, but a higher-than-expected prevalence of premutation and "gray zone" alleles may complicate analysis of the public health burden of testing, according to results from a study by Flora Tassone, PhD, from the University of California, Davis, and colleagues,
published online December 21 in
Genome Medicine.
A Spectrum of Mutations and Manifestations
FXS is the most common cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). It is caused by extra CGG repeats in the first exon of the fragile X mental retardation 1 (
FMR1) gene, which encodes part of the 5' untranslated region of the corresponding mRNA.
Most people have 29 or 30 CGG repeats in the gene. In individuals with the full mutation, exceeding 200 repeats, extended methylation turns off the gene, which adversely affects synaptic plasticity. Affected children have ID, behavior problems, social deficits, and ASD.
Individuals with the premutation have between 55 and 200 copies of the CGG repeat. Because the extended allele is unstable and can grow with generations, premutation carriers are at increased risk of having children with FXS. Premutation carriers are also at elevated risk of developing childhood- or adult-onset neurological disorders, including ASD, attention-deficit/hyperactivity disorder, anxiety, and depression.
Women with the premutation face a 20% risk of developing fragile X–associated primary ovarian insufficiency, and 40% of older male and between 8% and 16% of older female premutation carriers develop fragile X–associated tremor ataxia syndrome. Others may develop milder neurological problems, such as neuropathy or balance disorders.
Individuals who have 40 to 54 repeats are in the "gray zone," which is not well understood but may increase risk for fragile X–associated tremor ataxia syndrome and fragile X–associated primary ovarian insufficiency, and "can be unstable when transmitted across generations," the authors explain. .
The prevalence in the general population of the full mutation is between 1:2500 and 1:8000 for females and 1:400 and 1:5000 for males, and the prevalence of the premutation is between 1:130 and 1:256 for females and 1:250 to 1:813 for males. Prevalence varies in different populations.
FXS Testing As Part of Newborn Screening
Although newborn screening recommendations in 2006 from the American College of Medical Genetics did not include FXS, encouraging results in early-phase clinical trials in toddlers as well as an improved polymerase chain reaction–based method to detect repeats suggest that newborn diagnosis may one day be actionable.
The authors report results of a pilot newborn screening study to assess the prevalence of different CGG repeat sizes in
FMR1. They analyzed 14,207 blood spots from newborns (7312 boys and 6895 girls) collected from November 2008 through May 2012 from the University of California Davis Medical Center; Rush University Medical Center in Chicago, Illinois; and the University of North Carolina Hospital in Chapel Hill. Parents of newborns found to have the premutation were offered a follow-up medical visit, confirmatory blood testing, and genetic counseling.
The study detected a single full-blown case; the sample was not large enough to find more. Prevalence of the premutation was 1:209 girls (95% confidence interval, 1:303 - 1:149) and 1:430 (95% CI, 1:736 - 1:268) in boys. The study found 33 girls and 17 boys with the premutation, with a mean CGG repeat number of 70, ranging from 55 to 130.
Prevalence for gray zone expansions was 1:66 for girls (95% CI, 1:80 - 1:54) and 1:112 for boys (95% CI, 1:145 - 1:88). The study found gray zone expansions in 105 girls and 65 boys, with a mean CGG repeat number of 48, ranging from 45 to 54. Whites had more gray zone expansions than Hispanics and blacks, but not significantly more.
The researchers conclude that implementation of newborn screening for fragile X mutations requires better understanding of the effects of intermediate repeat numbers and analysis of the effect of informing families about these uncertain findings.
Prevalence Results "Not Surprising," but Study Raises Ethical Dilemma
"It's not surprising that the study found a higher prevalence of the premutation than has been previously reported, because the screening method allowed more precise quantification of the alleles using a next-generation [polymerase chain reaction] patented by Asuragen," Dejan Budimirovic, MD, director of the Fragile X Clinic at the Kennedy Krieger Institute in Baltimore, Maryland, told
Medscape Medical News. He agrees with the researchers' call for more studies of clinical outcomes associated with the premutation. Dr. Budimirovic was not involved in the study.
Michael Tranfaglia, MD, medical director of the FRAXA Research Foundation, who was also not involved in the study, cites the uncertainties associated with the premutation and gray zone state as challenges to newborn screening. "A premutation confers risk of some things, but nothing certain, as is the case with the full mutation, which causes developmental disorders in all males. This information could be useful for family planning and other major decisions later in life, but exactly how to best present this information is unclear," he told
Medscape Medical News. Gray zone alleles, he adds, present an ethical quandary, because associated risks are unclear. "It's uncertain whether 'gray zone status' should be reported to families, given our current understanding."
The study was supported by the National Center for Advancing Translational Sciences, the Eunice Kennedy Shriver National Institute for Child Health and Human Development, and the Centers for Disease Control in conjunction with the Association for Prevention Teaching and Research. One author has led treatment trials for autism and FXS and/or consulted for Roche, Novartis, Seaside Therapeutics, Forest, and Curemark. The remaining authors, as well as Dr. Budimirovic and Dr. Tranfaglia have disclosed no relevant financial relationships.
Genome Med. Published online December 21, 2012.
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