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fact
sheet
FMR1
and the Fragile X Syndrome
Dana C. Crawford
zbn9@cdc.gov
HuGE Review
Published
July, 2001
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FMR1
Gene |
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The fragile X
mental retardation-1 (FMR1) gene, located at Xq27.3, codes for the mRNA-binding
fragile X mental retardation protein (FMRP). FMRP is thought to
shuttle select mRNAs between the cytosol and nucleus and is highly
expressed in the brain, testes, ovaries, esophageal epithelium, thymus, eye, and
spleen. |
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Prevalence of
Gene Variants |
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The 5’ untranslated region of FMR1 contains a polymorphic CGG
(cytosine-guanine-guanine) repeat that can be categorized into four
classes based on the size of the repeat: common (6-40 repeats),
intermediate (41-60 repeats), premutation (61-200 repeats), and full
mutation (>200-230 repeats). The full mutation is the
disorder-causing form of the repeat, and the premutation is the carrier
form of the repeat. To date, all population-based estimates for the
fragile X full mutation are derived from the screening of a target
population such as a special education population. The findings are
then extrapolated to the general population with the assumption that all
males affected by the fragile X syndrome will be found among the targeted
population. Based on this screening scheme, the prevalence of the
full mutation in Caucasian populations is approximately 1 in 4,000 males
to 1 in 6,000 males, with point estimates ranging from 1 in 3,717 males to
1 in 8,918 males. Little information exists for other ethnic/racial
groups; however, population-based estimates in admixed, African-derived
populations suggest that the prevalence of the full mutation may be 1 in
2,500 males. No study has determined the prevalence of the full
mutation among females in the general population. Based on the
prevalence of the full mutation in males, 1 in 8,000 females to 1 in 9,000
females in the general population may be affected by the fragile X
syndrome.
For premutations (61-200 repeats), the
estimates for Caucasian females range from 1 in 246 to 1 in 468 in the
general population. To date, the smallest premutation to hyperexpand
to the full mutation in a single generation is 59 repeats. If the
threshold for premutations were lowered to 55-200 repeats, the prevalence
among Caucasian females can be as high as 1 in 116, depending on the
population studied. For Caucasian males, the prevalence of the
premutation (61-200 repeats) is probably between 1 in 1,000 to 1 in 2,000
in the general population. No estimates exist for other
racial/ethnic groups.
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Disease
Burden |
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The fragile X
syndrome is the most common form of inherited mental retardation and
accounts for approximately 40% of cases with X-linked mental retardation.
Other characteristics of the fragile X syndrome include a wide range of
cognitive, behavioral, and physical features such as variable IQ (profound
to mild mental retardation), autistic-like features, hyperactivity,
increased testicular volume, macrocephaly, and large ears. Females
are less severely affected, presumably because of X-inactivation. In
the United States, a child with the fragile X syndrome is eligible for
early intervention and special education services. A screening study
in a U.S. public special education population suggests that approximately
1 in 400 males receiving special education services are affected by the
fragile X syndrome.
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Interactions |
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No gene-gene or
gene-environment interactions have been identified. However, such
interactions are possible, because the fragile X syndrome clinical
phenotype is variable and cannot be explained by the CGG repeat size or
the variability of FMRP. Also, approximately 21% of premutation
female carriers experience premature ovarian failure (POF: cessation
of menses prior to 40 years). Full mutation female carriers do not
experience POF; therefore, many researchers speculate that the large CGG
repeat in the transcript is responsible for this phenotype. However,
the mechanism remains to be elucidated.
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Laboratory
Tests
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The Quality
Assurance Subcommittee of the American College of Medical Genetics
Laboratory Practice Committee states that the laboratory tests which
effectively detect and measure the CGG repeat are more than 99% sensitive
and 100% specific. These methods do not detect point mutations or
deletions, which account for less than 1% of the fragile X
syndrome-causing mutations. Also, intermediate alleles are
considered inconclusive for carrier testing. Much research is needed
to understand which intermediate alleles are susceptible to hyperexpanding
to the full mutation in the next generation for the purpose of genetic
counseling.
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Population
Testing |
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In 1994, a working
group for the American College of Medical Genetics published guidelines
for making referrals for fragile X testing. These included testing
any person with unexplained mental retardation, developmental delay, or
autism, especially if physical or behavioral characteristics commonly
associated with the fragile X syndrome are evident. The working
group also recommended carrier testing on the basis of a family history of
unexplained mental retardation. The working group currently does not
recommend population carrier screening. Unlike the United States,
Finland and a few medical centers in Israel currently offer a fragile X
test to women who are pregnant. If identified as a carrier of the
fragile X premutation or full mutation, these women are offered prenatal
diagnosis. Preliminary results suggest that participation in both
the initial carrier testing and prenatal diagnosis is high (Finland: 85%
and 100%, respectively).
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References |
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Crawford DC, Acuña JM,
Sherman SL. FMR1 and the fragile X syndrome: human genome
epidemiology review. Genet Med (in press).
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Warren ST, Sherman SL.
The fragile X syndrome. Chap 64 in: Scriver C, Beaudet A, Sly
W, Valle D, editors. The metabolic basis of inherited disease. New
York: McGraw Hill, 2001:1257-89.
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Maddalena A, Richards CS,
McGinniss MJ, Brothman A, Desnick RJ, Grier RE, Hirsch B, Jacky P, McDowell
GA, Popovich B, Watson M, Wolff DJ. Technical standards
and guidelines for fragile X: the first of a series of disease-specific
supplements to the standards and guidelines for clinical genetics
laboratories of the American College of Medical Genetics. Genet Med
2001;3:200-5.
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Hagerman RJ, Cronister A.
Fragile X syndrome: diagnosis,
treatment, and research. Baltimore: Johns Hopkins University Press,
1996:3-88.
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Mazzocco MMM. Advances in
research on the fragile X syndrome. Ment
Retard Dev Disabil Res Rev 2000;6:96-106.
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Web sites |
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The National Fragile X
Foundation
FRAXA Research
Foundation
Carolina
Fragile X Project
GeneClinics
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