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Article by: Shauna White

Large Cohort Study Shines Light on the Fragile X Syndrome Gray Area


Fragile X syndrome (FXS) is a rare genetic condition that causes learning disabilities, cognitive delays and shares some similarities to autism. While the syndrome was first described by J. Purdon Martin and Julia Bell in 1943 [1], it was in 1969 that Herbert Lubs gave the syndrome its name. Lubs observed a defect near the end of the arms of the X chromosomes from related patients with intellectual disabilities. Because the defect made the end of the X chromosome appear like it was dangling by a thread, Lubs named the syndrome “Fragile X”. [2]  Lubs’ finding was ignored until 1991 when new technology and a lot of hard work allowed an international team of scientists to identify the mutation that causes FXS.  

Nearly all cases of FXS are caused by a copy number variation (CNV) mutation in the FMR1 gene. A CNV occurs when a portion of a gene is repeated over and over again. In the case of the FMR1 gene, a DNA segment known as a CGG triplet repeat is normally repeated between 5 and 40 times. In people with FXS there are more that 200 CGG repeats. This long string of repeated nucleotides causes the fragile appearance of the X chromosomes of FXS patients. The abnormally high number of repeats turns off the FMR1 gene which leads to nervous system dysfunction and symptoms of FXS.

People with 55-200 repeats of the CGG segment are classified as having an FMR1 gene premutation. While FXS is classified as a rare disease, the premutation CNV is much more common in the general population than the full FXS CNV. People with the premutation often exhibit symptoms that are distinct from FXS and are considered FXS carriers as their children are at a higher risk of being born with FXS.

If an individual has 45-55 CGG repeats in their FMR1 gene, they fall into what is referred to as the gray zone. Very little research has focused on the gray zone mutation and consequently there is disagreement within the research community on the boundaries of the gray zone, the prevalence of the CNV and the symptoms and risk factors affecting gray zone carriers.

In an effort to determine the prevalence of the FMR1 premutation and gray zone in a large American population, Dr. Marsha Seltzer and her research team from University of Wisconsin-Madison accessed data and study subjects from the Wisconsin-Longitudinal Study (WLS). The WLS contains a random sample of 10,317 men and women who graduated from Wisconsin high schools in 1957. In 2006 and 2007, the original graduates and their siblings were contacted and a high proportion of the study subjects agreed to provide their DNA using an Oragene saliva collection kit. The researchers explained that “oragene kits were chosen because of their ability to be used in a mailback protocol (e.g. no need for immediate freezing) and their high average DNA yield.” [3]

To determine the FMR1 CGG triplet repeat number in each of the 6,747 respondents, Dr. Seltzer and her team devised a PCR based high throughput platform that allowed them to process 96 samples at a time. They found that 1 in 38 of the respondents carried the gray zone CNV and 1 in 250 of respondents carried the premutation. Using a combination of telephone interviews, mailback questionnaires, and existing demographic data for this cohort, the researchers looked for links between CGG repeat length and previously reported symptoms
associated with the premutation.

Both men and women with the premutation were more likely to report feeling dizzy, faint or numbness, when compared to the control group. They also found that female premutation carriers had their final menstrual period almost 3 years sooner than controls. In addition, nearly a quarter of parents with the premutation had a child with a disability, compared to just over one tenth of parents with normal repeat lengths. All of these findings confirmed previously published data on FMR1 premutation carriers.

While it’s gratifying as a scientist to prove your hypothesis is correct, sometimes the most interesting results are unexpected. While analyzing the demographic information collected from this cohort, they noticed that premutation carriers were more likely to be divorced than the control group. The researchers looked at a link between the divorce rate and having a child with a disability but the data did not support a relationship.  In the interest of science, further investigation with a different cohort might be worth pursuing.

The findings of the Wisconsin-Longitudinal Study helped determine the prevalence, risk factors and symptoms of the FMR1 premutation and gray zone mutation in a large population. The results are particularly interesting because the prevalence is more common than originally thought and further research is needed to understand the impact the premutation CNV has on the general population. That is why, in my opinion, the development of a large scale screening method for FMR1 CGG repeats is perhaps the most important result to come out of this work.

Request free trial kits of any DNA Genotek saliva kit


[1] Martin JP and Bell J. A Pedigree of Mental Defect Showing Sex-Linkage. J Neurol Psychiatry. 6(3-4):  154–157 (1943)

[2] Lubs, HA, Jr. A Marker X Chromosome. Am. J. Hum. Genet. 21(3): 231-244 (1969)

[3] Seltzer MM et al. Prevalence of CGG expansions of the FMR1 gene in a US population-based sample. Am J Med Genet B Neuropsychiatr Genet. 159B(5):589-597 (2012).

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