Fragile X syndrome: Is now the time for population screening?

May 1, 2010

Recently published
in Genetics in Medicine, the journal of the American College of
Medical Genetics (ACMG), were results of a study that validated a new
technique for detecting carriers and newborns with Fragile X syndrome —
an important step forward in longstanding efforts to develop a better
means of detecting genetic carriers of this disorder. The technique,
which uses triplet-primed polymerase chain reaction (PCR) with capillary
electrophoresis (CE) on specimens of blood, saliva, and dried
blood-filter paper spots, can replace the Southern blot technique in 99%
of cases without compromising accuracy.

Fragile X syndrome is the leading inherited cause of mental
retardation and the most commonly known single-gene cause of
autism. It is caused by a genetic mutation of the Fragile X
mental-retardation 1 (FMR1) gene residing on the so-called
“female” X chromosome. Because men have only one copy of the X
chromosome, males who inherit a mutation are twice as likely as
females to be affected. The symptoms can include profoundly
delayed speech, mental impairment, behavior problems, and
distinctive physical traits (e.g., facial features [long faces,
prominent ears], connective tissue problems, double-jointedness,
and macroorchidism). Although females are less likely to be
affected, they, too, can suffer from mental retardation and
other effects. Many affected individuals fulfill the criteria
for autistic-spectrum disorder.

Despite these challenges, population screening for Fragile X syndrome, like cystic fibrosis, would confer important benefits.

Because Fragile X is linked to the X
chromosome, a woman who is genetic carrier can pass the syndrome
to her offspring, regardless of the father's genetic
characteristics. By comparison, two prevalent genetic disorders,
cystic fibrosis and Tay-Sachs disease, can occur only when both
mother and father are carriers.

Screening demands medical, social, ethical resolutions

Both the ACMG and the American College of
Obstetricians and Gynecologists (ACOG) have recommended
population-based carrier screening for cystic fibrosis among
Caucasians and for Tay-Sachs disease among Ashkenazi Jews.
Despite the greater prevalence of Fragile X at-risk couples,
guidelines generally recommend that women with a family history
of mental retardation be tested for their Fragile X-carrier
status. Recommendations do not exist for population or newborn
carrier screening.

At the 2010 ACMG meeting, a presentation
revealed that the carrier frequency for Fragile X syndrome is
one in 236 women in the general U.S. population. This means that
a population-based carrier-screening program for the disorder
would identify greater than three times more at-risk couples
than either cystic fibrosis (1:784) or Tay-Sachs (1:900)

To a great extent, technical limitations
inhibiting high-throughput laboratory testing have prevented
population-wide testing for Fragile X syndrome. Now that
high-throughput screening is feasible technologically, a number
of medical, social, and ethical issues must first be considered
by ACMG and ACOG before recommendation for wide screening. These
issues — little changed since interest in carrier screening
initially emerged with the introduction of the first DNA lab
test for Fragile X syndrome in the early 1990s — can broadly be
categorized as 1) educating society and healthcare professionals
and 2) the potential for social bias.

 Education about a complex, multifaceted disorder

One of the challenges in implementing
screening revolves around the variable presentation of Fragile X
syndrome. Carrier status and the degree of disability depend
largely on the number of times a particular pattern of DNA
recurs on the FMRI gene.

The frequency of this pattern determines
if an individual has a premutation or a full mutation. A woman
is a carrier whether she has a full or a premutation. Men with a
premutation may escape developmental disorders, yet still be at
risk of developing Fragile X-associated tremor/ataxia syndrome
(FXTAS), a condition which can mimic Parkinson's disease later
in life. Twenty percent of women with a premutation may
experience premature ovarian insufficiency (POI), which prompts
early onset of menopause.

Given these complex issues, how can the
medical community educate the public about the disorder? And
what role can the laboratory play in educating the various types
of physicians who may evaluate these patients and seek the
laboratory's interpretative counsel?

Potential for social bias

Another key challenge relates to the
potential for social bias. While there is no cure for Fragile X
syndrome, early intervention to help the developing brain may
benefit some affected children. Yet, the degree of disability is
highly variable. Would newborn screening be beneficial in
promoting early intervention, or would it cause children to grow
up confronted with damaging prejudices? Would parents be
inclined to display confidence-eroding bias toward a child who
harbors a premutation, which may carry little risk of
developmental disability?

Couples who know their risk for the
disorder can make more informed decisions. Notably, a recent
study found that diagnoses of children with Fragile X often
occur after the age of three. By then, unknowing parents may
have given birth to other affected siblings.

Given these complex issues, how can the medical
community educate the public about the disorder? And what
role can the laboratory play in educating the various types
of physicians who may evaluate these patients and seek the
laboratory's interpretive counsel?

Moreover, children who are diagnosed
early can receive proper educational and social support. And in
the future, medications — including certain pharmaceutical
agents now in clinical trials — may be targeted specifically to
children with Fragile X syndrome.

Finally, men and women who understand the
genetic cause of their FXTAS and POI may be spared the confusion
and anxiety that patients often feel when a definitive diagnosis
eludes them. Further studies to validate the approach described
here are necessary before medical guidelines are likely to

Feras M. Hantash, MS, PhD,
principal scientist in charge of molecular-genetics R&D for Quest
Diagnostics Nichols Institute — the esoteric R&D testing center of Quest
Diagnostics — was instrumental to the development of the company's
XSense Fragile X syndrome test. Dr. Hantash was lead investigator on
“Qualitative assessment of FMR1 (CGG) in triplet repeat status,” a study
to validate the technique published in the March 2010 issue of
Genetics in Medicine.

Editor's note: The
abstract of this study mentioned by Dr. Hantash is online at:

Published: May, 2010