UC Davis researchers will begin large-scale screening of newborns this fall for the gene mutation that causes fragile X syndrome, the most common inherited culprit for a wide spectrum of developmental disorders including mental retardation and autism.
The screening is part of a comprehensive study that will determine the occurrence of different forms of the mutation in the general population. It also aims to gauge the benefits of early knowledge about children who test positive for the condition, said Paul Hagerman, professor of biochemistry and molecular medicine at the UC Davis MIND Institute.
Fragile X syndrome results from expansion of a repeated 3 nucleotide DNA sequence (CGG) in a gene located on the X chromosome, according to The National Fragile X Foundation website.
Depending on the number of repeats, the gene is considered to be normal, premutation or full mutation. The full mutation shuts off production of an important protein, resulting in fragile X symptoms such as intellectual disabilities, behavior problems, low muscle tone and some physical abnormalities.
“We only have a very imprecise understanding of how that repeat number dictates how severe their diseases will be or whether they’re going to get the problem or not,” Hagerman said.
Current estimates put the frequency of fragile X at 1 in 3,600 for males and 1 in 4,000 for females. One in 800 males and 1 in 260 females carry an inheritable premutation in the fragile X gene. However, the figures are based on previous studies that were biased towards populations that are mentally retarded, and more recent studies suggest the prevalence of the mutations and disease are higher, said Flora Tassone, lead study investigator and associate research biochemist in the department of biochemistry and molecular medicine.
“There isn’t a single large-scale population-based screen to date that’s been performed in the U.S.,” Hagerman said. “So all the conclusions and the policy decisions made in this country are done in the absence of good numbers for how common this disorder is.”
Starting later this year, all newborns at UC Davis Medical Center will have the option to undergo blood spot tests for fragile X screening. Researchers will collect the blood samples over a five-year period and use a polymerase chain reaction (PCR) technique that Tassone and Hagerman optimized to detect expansion of the CGG repeat in the fragile X gene.
This screening method is improved from previous methods in that it’s faster, cheaper, requires a smaller amount of blood DNA and can reliably identify the status of the fragile X gene in everyone, Tassone said. Additionally, all participants in the study who test positive for a mutation will receive a clinical follow-up including evaluations and access to appropriate intervention treatments for problems caused by fragile X.
“Part of the pilot study is to see just how effective knowledge of individuals at risk is and how effective early intervention is,” Hagerman said.
The importance of widespread screening is underscored by the implications of having a fragile X mutation in the family.
“On average, we expect to see at least six additional individuals affected by fragile X in each family identified by a baby who is positive,” said Randi Hagerman, medical director of the MIND Institute, in an e-mail interview.
Fragile X carriers will likely be identified, and they are susceptible to another range of ailments, Tassone said. The premutation can cause premature ovarian insufficiency in females resulting in infertility and early menopause. In older males and some older females, it can cause FXTAS, a degenerative disease similar in its symptoms to Parkinson’s.
Family planning could be another issue as female carriers are at risk of having children with fragile X.
About 30,000 newborns will be screened during the study, including those participating at Rush University Medical Center in Chicago as well as the UC Davis Medical Center.
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