Journal of Genetic Counseling, Vol. 14, No. 4, August 2005 ( c ? 2005)
Genetic Counseling for Fragile X Syndrome: Updated
Recommendations of the National Society of
Allyn McConkie-Rosell,1,7Brenda Finucane,2Amy Cronister,3Liane Abrams,4
Robin L. Bennett,5and Barbara J. Pettersen6
These recommendations describe the minimum standard criteria for genetic counseling and
testing of individuals and families with fragile X syndrome, as well as carriers and potential
carriers of a fragile X mutation. The original guidelines (published in 2000) have been revised,
replacing a stratified pre- and full mutation model of fragile X syndrome with one based on a
continuum of gene effects across the full spectrum of FMR1 CGG trinucleotide repeat expan-
sion. This document reviews the molecular genetics of fragile X syndrome, clinical phenotype
(including the spectrum of premature ovarian failure and fragile X-associated tremor-ataxia
syndrome), indications for genetic testing and interpretation of results, risks of transmission,
family planning options, psychosocial issues, and references for professional and patient re-
sources. These recommendations are the opinions of a multicenter working group of genetic
counselors with expertise in fragile X syndrome genetic counseling, and they are based on
clinical experience, review of pertinent English language articles, and reports of expert com-
mittees. These recommendations should not be construed as dictating an exclusive course of
management, nor does use of such recommendations guarantee a particular outcome. The
professional judgment of a health care provider, familiar with the facts and circumstances of
a specific case, will always supersede these recommendations.
KEY WORDS: fragile X syndrome; genetic counseling; genetic testing; premature ovarian failure;
FXTAS; premutation; FMR1; prenatal diagnosis; National Society of Genetic Counselors; practice
counselors and other health care professionals who
1Duke University Medical Center, Durham, North Carolina.
2Elwyn Training and Research Institute, Elwyn, Pennsylvania.
3Genzyme Genetics, Phoenix, Arizona.
4Liane Abrams: National Fragile X Foundation, San Francisco,
5Medical Genetics, Department of Medicine, University of
Washington, Seattle, Washington.
6Genetic Counseling of Central Oregon, Bend, Oregon.
7Correspondence should be directed to Allyn McConkie-Rosell,
PhD, CGC, Box 3525, Division of Medical Genetics, Duke
University Medical Center, Durham, North Carolina 27710;
and their families.
The genetic counseling recommendations of the
National Society of Genetic Counselors (NSGC) are
developed by members of the NSGC to assist practi-
and is based on a review and analysis of the profes-
sional literature. The information and recommenda-
tions reflect scientific and clinical knowledge current
1068-0667/05/0800-0249/0 C ?2005 National Society of Genetic Counselors, Inc.
250 McConkie-Rosell, Finucane, Cronister, Abrams, Bennett, and Pettersen
as of the submission date and are subject to change
as advances in diagnostic techniques, treatment, and
ations in practice, taking into account the needs of
the individual patient and the resources and limita-
tions unique to the institution or type of practice,
may warrant approaches, treatments, or procedures
alternative to the recommendations outlined in this
not be construed as dictating an exclusive course of
management, nor does use of such recommendations
guarantee a particular outcome. Genetic counsel-
ing recommendations are never intended to displace
a health care provider’s best medical judgment
based on the clinical circumstances of a particular
The authors consisted of experts in the field of
genetic counseling for fragile X syndrome. Review
and input was also sought from medical specialists
with expertise in fragile X syndrome and patient ad-
vocacy groups. The authors searched the MEDLINE
and PsycINFO databases for relevant English lan-
guage medical and psychosocial literature between
1999 and 2004, including seminal articles from earlier
dates. Key words included: fragile X syndrome, ge-
netic counseling, psychosocial assessment gene test-
ing, premature ovarian failure, prenatal diagnosis,
lines and policy statements published by the Ameri-
can College of Medical Genetics (Sherman, Pletcher,
and Driscoll, 2005; Maddalena et al., 2001), and
genetic counseling guidelines developed by genetic
1998) were also reviewed. This literature is based on
clinical experience, descriptive studies and/or reports
of expert committees. The literature was reviewed
and evaluated for quality according to the categories
outlined by the U.S Preventive Services Task Force
(1995). The rating of supporting literature for this
recommendation is class III: Opinions of respected
authorities, based on clinical experience, descriptive
studies, or reports of expert committees.
ship includes genetic counselors, physicians, nurses,
vised document was reviewed by the NSGC attorney
and the NSGC Ethics Subcommittee and no conflicts
with the NSGC Code of Ethics or issues regarding le-
gal liability were identified in the final document. The
final document in March, 2005.
INTRODUCTION TO FRAGILE X SYNDROME
In 1969 Lubs reported the presence of an
abnormal “marker X” chromosome in a family with
males with mental retardation following an X-linked
pattern (Lubs, 1969). It was not until 1977 that
Sutherland was able to show that the expression of
the marker X chromosome was inextricably linked to
low folate concentrations in the cell culture medium
(Sutherland, 1977). With this riddle solved, a rela-
tively reliable cytogenetic test soon became available
to distinguish the subgroup of males with the newly-
named fragile X syndrome. Throughout the 1980s, as
molecular advances put researchers within reach of
the exact location of the fragile X gene, linkage anal-
ysis allowed relatively accurate carrier and prenatal
testing for some families (Shapiro et al., 1988). In
1991 the gene responsible for fragile X syndrome was
identified (Oberle et al., 1991; Verkerk et al., 1991;
Yu et al., 1991), allowing highly reliable diagnostic,
prenatal, and carrier testing. Despite these advances,
several aspects of genetic counseling for fragile X
syndrome remain challenging, including the interpre-
tation of intermediate alleles and the widely variable
clinical prognosis, particularly in females with fragile
male-to-male transmission of the fragile X mutation,
genetic counselors should be wary of citing absolutes.
As the understanding of the clinical phenotype in
both males and females continues to evolve, the
previously sharp clinical distinctions between pre-
and full mutations have become more fluid. Recently,
Hagerman and Hagerman (2004) proposed replacing
the stratified pre- and full mutation model of fragile
X syndrome with one based on a continuum of gene
effects across the full spectrum of repeat expansion.
FMR1 Gene and FMR1 Protein (FMRP)
The FMR1 (Fragile X Mental Retardation-1)
gene is characterized by a repetitive CGG trinu-
cleotide sequence located in the 5?promoter region,
which, in most people in the general population, is
repeated from 6 to 50 times. Two abnormal FMR1
states have been identified in association with fragile
Genetic Counseling for Fragile X Syndrome 251
X syndrome, both involving unstable expansions in
the number of CGG repeats. Premutation alleles are
mutations are unstable in females, and may undergo
further size expansions during oogenesis and postzy-
gotic mitosis. CGG sequences with more than 200 re-
associated with fragile X syndrome in both males and
females. This may be reported as a smear indicating a
range of repeat sizes all above 200. Mutations of this
size are usually hypermethylated and do not produce
FMR1 mRNA or protein. No instance of a child with
a “new” FMR1 full mutation inherited from a par-
ent with a normal size allele has been documented.
Therefore, all mothers of children shown to have the
full mutation are assumed to be obligate carriers of
either a pre- or full FMR1 mutation.
The frequency of individuals with full mutations
who are mosaic in lymphocytes for either the number
of CGG repeats (size mosaics) or observed methyla-
tion pattern (methylation mosaics), is approximately
12% and 6%, respectively (Rousseau et al., 1994a).
Methylation mosaics have both methylated and un-
saics demonstrate a variety of allele sizes (full, pre-
mutation, or normal-sized alleles) on Southern Blot
The FMR1 gene in its normal state produces a
protein that is thought to play a key role in both pre-
and postnatal brain development. Fragile X Mental
Retardation Protein (FMRP) is expressed in a variety
of tissues, but it is most abundant in neurons (Devys
et al., 1993). Hypermethylated FMR1 full mutations
inhibit FMRP production as a consequence of tran-
scriptional repression (Pieretti et al., 1991; Sutcliffe
et al., 1992), resulting in clinical symptoms. Based
on research using the fragile X knockout mouse, it
has been hypothesized that FMRP may play an im-
portant role in mGluR-mediated plasticity; a process
by which dendrites in the brain mature (Bear et al.,
ing the balance between how the brain strengthens
(Long-Term Potentiation) or eliminates (Long-Term
Depression) connections between neurons. The ab-
sence of FMRP results in unregulated activation of
mGluR Long-Term Depression. Therefore, the brain
is unable to establish and maintain strong synapses
required for learning and memory. Research investi-
proteins is providing new hope for the treatment of
fragile X syndrome and related disorders.
ing specific prevalence figures for the fragile X full
mutation, a range from 1 in 4000 to 1 in 6000 has been
documented in population studies (Crawford et al.,
2002; Morton et al., 1997; Turner et al., 1996). The
prevalence of affected males in cohorts of children
et al., 1999; De Vries et al., 1997; Gonzalez-del Angel
Meadows et al., 1996; Murray et al., 1996; Syrrou et
al., 1998). The range may be explained by the pop-
ulations studied and the diagnostic selection criteria
used (e.g., special education classroom, autism, non-
syndromic mental retardation).
Rousseau et al. (1995) concluded that the preva-
lence of female carriers of an FMR1 premutation
(>54 CGG repeats) is approximately 1 in 259, and
the prevalence of male carriers of an FMR1 premu-
tation is approximately 1 in 755. A study of over
14,000 women in Israel found 1 in 113 women had re-
Alhadef et al., 2001). The women screened had no
known family history of mental retardation and were
representative of the diverse Jewish population liv-
ing in Israel. No systematic study has been done to
accurately estimate the prevalence of the pre- or full
mutation carriers in different ethnic or racial groups.
Nevertheless, these figures provide some guidelines.
Diagnosing Fragile X Syndrome
The diagnosis of fragile X syndrome requires the
mal number of CGG trinucleotide repeats accompa-
are detected by PCR and Southern Blot analyses (see
Fu et al., 1991; Heitz et al., 1991; Oberle et al., 1991).
Rare individuals with fragile X syndrome who have
deletions of all or part of the FMR1 gene (Gedeon
et al., 1992; Tarleton and Saul, 1993; Wohrle et al.,
1992), or point mutations within it (De Boulle et al.,
1993), account for fewer than 1% of individuals with
fragile X syndrome. The identification of deletions
will vary depending on the probes used in Southern
Blot analysis. To detect point mutations, however,
direct sequencing of the FMR1 gene (which may only
be available on a research basis) may be necessary.
252 McConkie-Rosell, Finucane, Cronister, Abrams, Bennett, and Pettersen
FMR1 Instability and Factors Affecting
CGG Repeat Expansion
The FMR1 gene contains a trinucleotide repeat,
composed primarily of CGG, in the 5?promoter re-
gion of the gene, outside the coding exons. Instability
of the repeat is the predominant mechanism disrupt-
ing the expression of the FMR1 gene, accounting for
The number of CGG repeats at the FMR1 locus is
variable in the general population, ranging from 6 to
∼50 (Brown et al., 1993; Fu et al., 1991; Nolin et al.,
1996; Reiss et al., 1994; Snow et al., 1993). The most
common number of repeats in an unexpanded FMR1
allele is 30 (Brown et al., 1993; Snow et al., 1993).
Individuals who carry premutation alleles are at
risk of passing the unstable mutation to successive
has been difficult to establish, but is thought to be
somewhere around 55–60 CGG repeats. It is impor-
tant to note, no expansion to a full mutation in one
generation has been reported with alleles containing
fewer than 59 CGG repeats (Nolin et al., 1996, 2003).
tors affecting FMR1 gene expansion in females (e.g.,
Fu et al., 1991; Nolin et al., 1996, 2003; Sherman et al.,
1996; Snow et al., 1993), and found that expansion of
the CGG repeat is influenced by the gender of the
carrier, the number of repeats, and the presence of
AGG interruptions within the repeat. The process by
which CGG repeat expansion occurs may be related
to difficulties in DNA replication of the repeat. Pre-
mutations may undergo expansion during oogenesis
in carrier females (Malter et al., 1997), and during
postzygotic mitosis in children who inherit the pre-
mutation from their mothers (Wohrle et al., 1993).
There are several reports of discordance in CGG re-
peat number and mental capacities between monozy-
gotic twins (Cantu et al., 1998; Helderman-van den
Enden et al., 1999; Tiberio, 1994). At this time, the
Table I. Percent Expansion to Full Mutation with Transmission of Maternal Premutation Allele (Number of Expan-
sions to Full Mutation/ Total Number of Pregnancies)
Maternal repeat size Nolin et al., 1996 Pesso et al., 2000 Toledano-Alhadef et al., 2001Nolin et al., 2003
Note. Data from Nolin et al. 2003.
exact mechanisms controlling the timing and extent
of CGG repeat expansion remain unknown.
Intermediate or gray zone are the terms used to
describe alleles that overlap the junction between the
normal and premutation ranges (approximately 45–
60) CGG repeats. Although alleles containing <55
repeats are generally considered stable, exceptions
have been reported (Brown et al., 1993; Crawford
et al., 2002). Unstable repeats in the intermediate size
range may be found in older generations (e.g. grand-
parent, great-grandparent) within fragile X families
and expansion of an intermediate allele of 44 to a
full mutation in two generations has been reported
(Terracciano et al., 2004). Because of the overlap of
normal and premutation alleles in the intermediate
range, it is difficult to interpret the significance of
the intermediate size alleles when they are found in
the general population. For this reason, results of a
single test in this range should be interpreted in the
context of the family and clinical history.
Multistep mutational models have been postu-
lated to account for changes in trinucleotide repeat
copy number from stable to unstable alleles (Ashley
and Sherman, 1995; Kolehmainen, 1994; Morton and
Macpherson, 1992). The risk for expansion of an
intermediate allele to a premutation (greater than 55
CGG repeats) may be related to the absence of AGG
Sequences of uninterrupted CGG repeats greater
than 33–39 may increase the risk for instability of ma-
ternal alleles upon transmission to offspring (Eichler
why alleles with the same CGG repeat number in the
intermediate range have different risks for instability.
Genetic Counseling for Fragile X Syndrome253
necessarily sufficient to induce instability in the inter-
mediate range (Nolin et al., 1996). Furthermore, the
determination of AGG repeats is not routine in most
molecular diagnostic laboratories. Regardless of the
mechanism, the risk for expansion to a full mutation
lies in the succeeding generations, as the offspring of
individuals with an intermediate allele, if inherited,
will have either a similar size allele or a premutation.
Mutations involving the trinucleotide repeat expan-
sion from normal alleles of less than about 50 repeats
to full mutations of >200 repeats are thought to
be produced over several generations (Ashley and
Sherman, 1995; Chakravarti, 1992; Kolehmainen,
Reversion, or contraction, is the term used to de-
scribe the phenomenon whereby an individual who
lele to his or her offspring. Contractions from premu-
in mother-to-daughter transmissions (Brown et al.,
imately one-third of daughters of males who carry
premutations have smaller premutations than their
fathers (Fisch et al., 1995). In addition, a study exam-
only alleles with premutation size repeats (Reyniers
et al., 1993).
Initially, individuals with fragile X mutations
were divided into binary categories of affected
(full mutations/methylated) and unaffected (premu-
mutations has long been appreciated. However, as
more is learned about the FMR1 mutation state, the
clinical spectrum of symptoms associated with frag-
ile X mutations should be seen as a continuum; indi-
viduals with premutations, as well as those with full
mutations, present with different but relevant mani-
festations of this genetic condition.
Males With Full Mutations
Males with full mutations may exhibit distinctive
facial characteristics including large and/or protrud-
ing ears, a long face, prominent forehead, mandibular
prognathism, strabismus, high arched palate with oc-
casional cleft palate, and macrocephaly. The facial
characteristics often develop over time, particularly
the prominent forehead and chin (Fig. 1). Connective
tissue findings include hyperflexible joints (particu-
feet, and mitral valve prolapse. Genital abnormalities
consist of macroorchism (testicles of more than 25ml
size) in postpubertal males.
The cognitive phenotype is characterized by a
spectrum of features including developmental delay
in the young child, mental retardation from mild to
severe, borderline IQ, and learning disabilities. The
behavioral phenotype includes attention deficit hy-
peractivity disorder (ADHD), speech and language
delay, anxiety, hand flapping, hand biting with accom-
panying hand calluses, tactile defensiveness, sensory
integration dysfunction, poor eye contact, persevera-
tive speech, echolalia, and coprolalia. Autistic spec-
trum disorders are common.
Females With Full Mutations
In general, females with full mutations have
milder features than males with full mutations but
they also exhibit a similar range of cognitive, behav-
of females with full mutations have some of the char-
acteristic physical features associated with fragile X
syndrome. Intellectual impairment is often milder in
females than in affected males. Cognitive functioning
can range from normal intelligence to learning dis-
abilities to mental retardation. Studies indicate that
(De Vries et al., 1996; Rousseau et al., 1991; Taylor
et al., 1994). Those females with full mutations who
have normal IQs may have learning disabilities or
mutism, shyness, poor eye contact, hyperactivity, and
impulsive behaviors (Sobesky et al., 1994; Keysor and
Mazzocco, 2002). It is not uncommon for females to
with math or excessive shyness without other major
phenotypic effects (Cronister et al., 1991).
Both male and female carriers of premuta-
tions were previously considered to be clinically
uninvolved. However, it is now known that these
254 McConkie-Rosell, Finucane, Cronister, Abrams, Bennett, and Pettersen
Fig. 1. Two brothers, ages 4 and 6 years, with characteristic facial features of fragile X syndrome.
individuals may present with a spectrum of clinical
findings including mild features of the fragile X syn-
drome, premature ovarian failure (POF), and fragile
Males With Premutations
Most males with premutations are unaffected by
fragile X syndrome. However, there are rare reports
of males with premutations who have mild manifes-
tations, including physical, cognitive, and behavioral
manifestations may be due to somatic mosaicism in
the target tissue.
Fragile X-associated tremor/ataxia syndrome
(FXTAS), a recently identified neurological condi-
intention tremor, cerebellar ataxia, Parkinsonism,
Genetic Counseling for Fragile X Syndrome255
and peripheral neuropathy. Brain MRI studies of af-
fected individuals are characterized by hyperintensi-
ties of the middle cerebellar peduncles (Hagerman
et al., 2001). The penetrance of FXTAS appears to
increase with age (Jacquemont et al., 2004). FXTAS
may ultimately prove to be a common manifestation
in males with premutations.
Females With Premutations
Females with premutations are usually unaf-
fected intellectually and physically, although cases
of females with premutations who are affected by
cognitive and/or emotional disorders have been re-
ported (Tassone et al., 2000). Females with pre-
mutations may have an increased incidence of
depression, social anxiety, and shyness (Franke et al.,
1998; Johnston et al., 2001). More commonly, females
with premutations are at increased risk for prema-
ture ovarian failure or ovarian dysfunction, accom-
panied by decrease in bone density (as observed in
many postmenopausal women) (Hundscheid et al.,
2003; Schwartz et al., 1994). (See the section on Re-
productive Issues.) There have been case reports
of females >50 years confirmed to have FXTAS
etrance and severity of FXTAS in females with pre-
mutations remains unknown.
Males With Mosaicism (Methylation or Size)
(See the section on Genotype/Phenotype Corre-
Males and Females With Intermediate Alleles
(45–54 CGG Repeats)
Individuals with intermediate size alleles are not
generally considered to be at risk for clinical man-
ifestations of either premutations or full mutations.
it is uncertain whether the clinical manifestations in
these boys are related to their genotype (Aziz, 2003).
Although CGG repeat length does not correlate
fluenced by a number of variables, including the gen-
der of the individual, methylation status, and tissue
when discussing the phenotype in a female with a full
mutation, as these individuals can show a full range
of phenotypic findings, from normal intellectual func-
to that found in full mutation males (De Vries et al.,
1996; Hagerman, 2002).
influence phenotypic expression (McConkie-Rosell
with methylation mosaicism may be higher, on aver-
age, than scores of those with fully methylated mu-
tations. Males with partially methylated premutation
size alleles in the upper range may have mild clinical
features. FMR1 protein may also be reduced in some
individuals who have large premutation alleles, com-
pared to protein levels of normal-sized alleles (Feng
et al., 1995; Hagerman et al., 1994; Lachiewicz et al.,
1996; Rousseau et al., 1994b; Smeets et al., 1995). The
biochemistry of FMR1 methylation is not well under-
stood, but the existence of the above reports suggest
that CGG repeat expansion and methylation are not
absolutely coupled. As with any type of mosaicism,
caution should be taken in interpreting results, as the
repeat copy number in one tissue (e.g., blood, chori-
status and repeat copy number in others (de Graaff
et al., 1995). FMRP studies, which may only be avail-
able on a research basis, may be helpful in evaluating
the impact of the mosaic pattern.
Currently, the penetrance of FXTAS as a func-
tion of CGG length is unknown; however this may be
of great mechanistic importance and is currently un-
der study (Jacquemont et al., 2004). There may be a
correlation between the number of CGG repeats and
the risk for premature ovarian failure in females with
premutations (Sullivan et al., 2005). (See the section
on Reproductive Issues.)
FMR1 DNA ANALYSIS
The FMR1 gene can be analyzed using both
Southern Blot and polymerase chain reaction (PCR)
analysis. Combining both methodologies, testing is
99% sensitive in detecting affected and carrier in-
dividuals, missing only the rare individual who has
fragile X syndrome because of a point mutation or
256 McConkie-Rosell, Finucane, Cronister, Abrams, Bennett, and Pettersen
testing performed on amniotic fluid cells or chorionic
villi is also available when a parent is a known carrier
section on Prenatal Diagnosis.) A positive FMR1 test
result is considered 100% specific. The exception to
this is detection of a CGG repeat in the intermediate
range (∼45–54 CGG repeats), which may or may not
be associated with fragile X syndrome in future gen-
erations. (See the section on Intermediate Alleles.)
Rousseau et al. (1991) were the first to pub-
lish methods for direct fragile X DNA diagnosis by
lele size(s) and methylation status, most laboratories
use two restriction enzymes, one of which is methyl-
sensitive, digesting only unmethylated DNA. Single
and double digest of extracted DNA are considered
ability to detect methylation, the use of two restric-
advantage of Southern Blot analysis is limited resolu-
tion, making it difficult to distinguish a normal-sized
allele from a premutation allele and accurately deter-
mine of premutation allele size for risk assessment.
PCR analysis as described by Erster et al. (1992)
and Brown et al. (1993) is the method of choice when
measuring subtle differences in allele size, and can
be used to distinguish alleles in the normal, inter-
mediate, and premutation range. When used alone,
PCR has the advantage of being less expensive than
and uses less DNA thereby allowing use of cheek
PCR methods cannot detect longer DNA sequences,
as PCR amplification favors smaller allele sizes. Be-
cause of the limitations of both Southern Blot and
PCR, most laboratories use both methods.
The American College of Medical Genetics pub-
lished technical standards and guidelines for fragile
X syndrome (Maddalena et al., 2001) that outline rec-
ommended elements to include in the fragile X DNA
report. In addition to stating the testing method(s),
definitions of categories for normal and mutation
(premutation, gray zone or intermediate, and full
mutation) and the corresponding CGG repeat range
should be included. Currently, there is variability
in CGG repeat sizing between laboratories. There-
fore, it is possible that a patient’s results could be
interpreted differently in separate laboratories when
CGG repeats are within the borders of the normal,
development will enable standardization among
laboratories and allow consistent detection of allele
sizes that differ by as few as one triplet repeat.
Fetal testing performed on amniotic fluid cells or
chorionic villi is available when a parent is a known
mutation carrier (ACMG, 1994). A full discussion of
TESTING AND SCREENING
The American College of Medical Genetics’
Policy Statement on fragile X syndrome (Sherman
et al., in press) recommends fragile X testing for:
1) Individuals of either sex with mental retar-
dation, developmental delay, or autism es-
pecially when associated with other physical
or a relative with undiagnosed mental retar-
2) Individuals with a family history of fragile X
syndrome or a family history of undiagnosed
mental retardation who are seeking repro-
ductive counseling. When there is no estab-
the affected proband is preferable to screen-
ing an unaffected relative. However, this is
not always feasible, especially in the prenatal
known FMR1 mutation carriers.
4) Individuals tested previously by cytogenetics
5) Women with reproductive or fertility prob-
lems associated with elevated FSH levels, es-
pecially if there is a family history of prema-
ture ovarian failure, fragile X syndrome, or
undiagnosed mental retardation.
6) Individuals with late onset tremor or cere-
bellar ataxia of unknown origin, particularly
Genetic Counseling for Fragile X Syndrome257
when there is a family history of movement
Genetic testing in minors is a complex ethi-
cal and social concern. Current guidelines state that
genetic testing of children is recommended only if
a clear benefit to the minor can be demonstrated
(ASHG/ACMG, 1995; National Society of Genetic
Counselors, 1995). Special issues exist in counseling
and testing minors which are covered in the section
on Genetic Counseling Issues.
Population-based screening has been proposed
to aid in identifying carriers and individuals affected
by fragile X syndrome. Although there is a growing
awareness of fragile X syndrome and the importance
of screening individuals with unexplained mental re-
tardation, the majority of carriers remain unaware of
their genetic status and reproductive risk (for review
see Sherman, 2002). Discussions of population-based
screening are complex because the implications of a
ing screened. Similarly, the genetic counseling for in-
dividuals identified through population-based carrier
based on how and when an individual was identified.
Palomaki (1994) and Finucane (1996) were
among the first to evaluate the feasibility of general
productive age. They found that fragile X syndrome
met population-based screening criteria, pointing out
in female fetuses with full mutations was problem-
atic and warranted further evaluation. Subsequent
research studies among women of reproductive age
have demonstrated the efficacy of fragile X screening
programs in identifying female carriers and affected
made more widely available to women in the general
population (Pesso et al., 2000; Ryynanen et al., 1999;
Toledano-Alhadef et al., 2001). Another publication
ing of pregnant women would identify 98% of fetuses
affected with fragile X syndrome annually and may
be cost-effective. A study by Skinner and colleagues
(2003), examining the attitudes and perspectives of
families with fragile X syndrome regarding screen-
fragile X syndrome available more broadly.
The genetic counseling that accompanies popu-
lation screening is critically important; there is some
evidence that without sufficient pre-test education,
women from the general population would be wholly
unprepared for positive carrier results (Anido et al.,
2005), and there are limited data on the psychological
impact of positive fragile X carrier results among
women at population risk to be FMR1 mutation
A common concern frequently expressed re-
garding FMR1 population-based screening is the is-
sue of identifying women with intermediate alleles.
One study reports the intermediate allele frequency
among women to be as high as 1 in 52 (Murray et al.,
ile X syndrome cite this high intermediate allele fre-
quency, and the presumed association with increased
anxiety and increased cost of testing, as a reason not
to implement such programs. To respond best to this
issue, protocols regarding identification and manage-
ment of intermediate allele carriers as well as patient
education programs outlining the implications of car-
rier testing should be developed prior to implement-
ing any population-based carrier screening program.
Newborn screening for fragile X syndrome is un-
der consideration. Supporters argue that early detec-
tion leads to early intervention and improved out-
comes (Bailey, 2004; Skinner et al., 2003). While there
are no data to confirm that early intervention affects
other disabilities to support the importance of early
intervention. Currently, however, newborn screening
for fragile X syndrome does not meet all of the es-
tablished screening criteria (Ciarleglio et al., 2003;
website US General Accounting Office, 2003). And,
ing test will need to be developed. Research is neces-
sary to investigate the medical, family, economic, and
ethical perspectives, and to delineate the advantages
and disadvantages of newborn screening for fragile X
The recently revised ACMG policy statement
on fragile X syndrome (Sherman et al., in press)
supports testing women with a family history of
258 McConkie-Rosell, Finucane, Cronister, Abrams, Bennett, and Pettersen
undiagnosed mental retardation. However, popula-
tion carrier screening was not recommended by the
ACMG, except as part of a well-defined research pro-
tocol. The ACMG policy statement cautioned against
genetic counseling issues including the broad pheno-
typic expression of the FMR1 mutation (including
Reproductive concerns for individuals with the
repeats yielding differences in fertility, prenatal diag-
nostic options, and genetic risk. Risk of expansion of
the unstable mutation is discussed in the section on
Expansion. This section focuses on fertility, precon-
ception options, prenatal diagnostic options, and the
implications for genetic counselors.
Premature ovarian failure (POF) is defined as
menopause occurring prior to the age of 40. The
risk of POF has thus far been found only in car-
riers of the FMR1 premutation and not in carriers
of the full mutation. Of women identified through
families with fragile X syndrome, approximately 13–
24% of women who are premutation carriers have
Sullivan et al., 2005). Conversely, premutation alleles
have been identified in 2% of women with idiopathic
sporadic POF and in 14% of women with a family
drome (Sherman, 2000). It is unknown whether the
risk of POF is higher in women with premutations
who have a family history of POF than in those who
Although a parent-of-origin effect regarding the
relative risk of POF has been reported (Hundscheid
et al., 2000) subsequent studies have failed to con-
firm this observation (Murray, Ennis, and Morton,
2000b; Sullivan et al., 2005; Vianna-Morgante and
Costa, 2000). There is no apparent correlation be-
tween the age at menopause and the X-inactivation
pattern among carriers of the premutation (Murray
et al., 2000a). There may be a correlation between the
number of CGG repeats and the risk for premature
et al., 2005). However, this relationship appears to be
nonlinear. Sullivan et al. (2005) suggest the risk for
POF may increase with increasing size repeat in pre-
mutation carriers in the range of 59–99, but that the
size alleles (>100).
The etiology of POF in carriers of the premuta-
tion is not known. It has been hypothesized that POF
is secondary to increased levels of the FMR1 tran-
script (Conway et al., 1995) observed in carriers of
the premutation (Tassone et al., 2000). Carriers of the
full mutation are thought to be unaffected because
they produce mRNA only from their normal allele.
The risk of POF has significant reproductive im-
plications. The onset is insidious and difficult to pre-
dict. The possibility of early menopause leading to
reduced fertility should be included in the genetic
counseling of women identified with a premutation.
chances of a successful pregnancy using preimplanta-
tion diagnosis secondary to a low yield of available
eggs (Platteau et al., 2002). Additionally, there is evi-
dence that premutation carriers may have hormonal
changes suggestive of early ovarian aging despite reg-
ular menstrual cycles (Welt et al., 2004).
tation do not appear to have reduced fertility. Inter-
estingly, the sperm of males with full mutations have
only premutation size repeats (Reyniers et al., 1993).
Although both pre- and full mutation males are ex-
pected to transmit premutation size alleles to their
daughters, there has been one case report of a male
daughter (Zeesman et al., 2004).
Individuals at risk for passing on fragile X mu-
tations to their offspring have a variety of pre- and
postconception options available. Some couples may
consider adoption in order to bypass the genetic risk.
for female and male mutation carriers, respectively.
Given the relatively high prevalence of fragile X
donors should be screened for fragile X mutations.
Genetic Counseling for Fragile X Syndrome259
Males at risk for passing on fragile X premutations to
their daughters may wish to consider sperm-sorting
techniques for sex selection of males. The efficiency
and reproducibility of these techniques are contro-
versial. Sex selection of spermatozoa by chromatin
differences has achieved significant enrichment of X-
or Y-chromosome bearing sperm, but clinical experi-
ence in humans remains limited (Sills et al., 1998).
Preimplantation genetic diagnosis (PGD) for
fragile X syndrome is possible but should be ap-
proached with caution. PGD for fragile X syndrome
sied embryos. Difficulties have been encountered in
to distinguish alleles, and amplification of the CGG
repeat (Platteau et al., 2002). In their single center
study of PGD for fragile X syndrome, Platteau et al.
(2002) found that the volume of eggs retrieved was
reduced, and only 55% of fertilized oocytes reached
the stage of embryo biopsy, thus leading to a signifi-
cantly reduced opportunity for pregnancy. Given the
potential for premature ovarian failure, premutation
carriers should be evaluated for subfertility prior to
consideration of PGD.
Linked polymorphic markers and direct detec-
tion of the expanded CGG repeat have both been
used for PGD (Apessos et al., 2001; Sermon et al.,
1999). Because the expanded CGG repeat is techni-
plantation diagnosis is based on the presence of the
normal maternal allele. Prior to attempting PGD, pa-
ternal and maternal allele sizes should be determined
by direct detection of CGG repeats, as well as linked
polymorphic markers when allele sizes differ by one
or zero, to ensure that the couple is informative.
Amniocentesis and Chorionic Villus Sampling
Prenatal diagnostic options for fragile X syn-
drome include amniocentesis and chorionic villus
sampling (CVS). Amniocentesis is both accurate and
reliable using the combined standard DNA diagnos-
tic methods of Southern Blot and PCR (Brown, 2002;
Brown et al., 1996b). The methylation status of the
FMR1 region and the number of CGG repeats in
Prenatal detection of the CGG repeat number for
fragile X syndrome using CVS is accurate and reli-
able; however, there are special considerations that
should be taken into account regarding the degree of
methylation of the placental tissue. The methylation
pattern observed in placental (CVS) tissue at 10–12
weeks gestation is incomplete and does not always
reflect that observed in the liveborn (Iida et al., 1994;
Willemsen et al., 2002). Because the clinical pheno-
tinguish large unmethylated premutations and small
methylated full mutations. The possibility of follow-
up amniocentesis to clarify the status of the fetus, if
the CVS result is indeterminate, should be discussed
as part of the pretest counseling. For both amniocen-
tesis and CVS, it may be helpful to determine both
maternal and paternal allele number either prior to
or concurrent with the prenatal testing. PCR analysis
of fetal and parental DNA can be useful in assessing
GENETIC COUNSELING ISSUES
Comprehensive genetic counseling for individu-
als and families in whom the diagnosis of fragile X
syndrome is suspected or has been made may require
ment on the part of the genetic counselor to follow
these families. If this commitment cannot be made,
referring the family to a genetic counselor or cen-
ter experienced with fragile X syndrome should be
The general assessment (medical, family, and
seling, management, and follow-up processes perti-
nent to fragile X syndrome are similar to those out-
lined in previous NSGC practice guidelines (Bennett
et al., 2002; McIntosh et al., 2000; Trepanier et al.,
2004). Genetic counseling for fragile X syndrome
should follow the recommendations in these guide-
lines with special attention given to genetic counsel-
ing methods and issues associated with X-linked dis-
orders (Bennett et al., 2002; McIntosh et al., 2000).
Issues specific to genetic counseling for fragile X syn-
drome are outlined in the following section.
When obtaining family, medical, and psychoso-
cial histories from patients and families, follow stan-
dard genetic counseling practice recommendations
(refer to www.ngc.gov). Targeted medical family
260 McConkie-Rosell, Finucane, Cronister, Abrams, Bennett, and Pettersen
Table II. Suggested Targeted Family History Questions for Fragile X Syndrome
Note for each relative, any history, and the age of onset of:
• Cognitive effects: Mental retardation, developmental delay, learning disabilities, specific problems with math.
• Speech delay or unusual speech pattern.
• Autistic spectrum disorders or autistic-like behaviors (gaze avoidance, repetitive behaviors, hand-flapping, hand biting, touch
• Attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD).
• Dysmorphic features—macrocephaly, large ears, long face, broad forehead, prominent jaw, strabismus.
• Features of loose connective tissue: hyperextensible joints, flat feet, hypotonia, mitral valve prolapse, large testicles, hernias,
recurrent ear infections.
• Neurologic symptoms: seizures, late-onset progressive tremor, ataxia, difficulty walking, balance problems, short-term memory loss,
loss of sensation in limbs.
• Mental illness/personality disorders: depression, schizophrenia, bipolar disorder, obsessive-compulsive disorder, schizoaffective
disorder, schizoid personality, etc.
• Behavioral problems: impulsiveness, anger outbursts, violent behavior, solitary behavior, counseling or medication for behavioral
• Shyness, social anxiety, excessive worrying, counseling or medication for emotional difficulties.
• Premature menopause, fertility problems.
history questions specific to fragile X syndrome are
included in Table II and are appropriate for use in
cases of suspected fragile X syndrome, families with
a confirmed diagnosis, and at-risk or known carriers.
Confirmed Diagnosis of Fragile X Syndrome
Genetic counseling sessions for families with
newly diagnosed fragile X syndrome offer opportuni-
Particular challenges inherent in genetic counseling
for fragile X syndrome include:
• the extremely variable expression of the
disorder, especially in females with the full
• the concepts of intermediate, premutation,
and full mutation alleles and the mechanism
of expansion including the multigenerational
mutation process and complexity inherent in
understanding the concept of carrier males in
an X-linked disorder;
• the variable recurrence risks based on size of
the premutation in the female carrier;
• the recent findings of FXTAS and POF in car-
riers of the premutation.
Genetic counselors should to be cognizant of
the fact that, in general, families are initially over-
whelmed, both emotionally and intellectually, by the
complexity of the disorder and its implications for
other family members. Suggested components for ge-
or confirmed diagnosis of fragile X syndrome appear
1. Discuss the clinical presentation and natural
history of fragile X syndrome in males and
2. Discuss the inheritance pattern and genetics
of fragile X syndrome and the approach to
and interpretation of results.
CGG repeat, methylation, sensitivity, and
amples of females and males with the pre-
mutation and full mutation, and the risk of
expansion/reversion in such cases.
to fragile X carriers (e.g., adoption, donor
egg or sperm, prenatal diagnosis, preim-
plantation genetic diagnosis); include eth-
ical concerns raised by such options, if
(e.g., limitations of CVS).
3. Be prepared to answer general questions re-
function of the FMR1 protein.
4. Discuss follow-up recommendations (e.g.,
identification and testing of at-risk family
members, scheduling follow-up visits).
Genetic Counseling for Fragile X Syndrome261
Table III. Printed and Online Resources on Fragile X Syndrome for Patients and Professionals
Family-oriented support groups
National Fragile X Foundation., http://www.fragilex.org
P.O. Box 190488
San Francisco, CA 94119-0988
FRAXA Research Foundation, http://www.fraxa.org
45 Pleasant St.
Newburyport, MA 01950
Braden, M. L. (2000). Fragile Handle with care: More about fragile X syndrome—adolescents and adults. Dillon, CO: Spectra.
Finucane, B., McConkie-Rosell, A., & Cronister, A. (2002). Fragile X syndrome: A handbook for families and professionals.
San Francisco, CA: Elwyn Inc., and the National Fragile X Foundation.
Harris-Schmidt, G., and Fast, D. (2004). The source for fragile X syndrome. East Moline, IL: LinguiSystems. Weber, J.D. (2000).
Children with fragile X syndrome: A parents’ guide. Bethesda, MD: Woodbine House.
Other online resources
The Arc’s Q&A on fragile X syndrome. Available at http://www.thearc.org/pdf/gbr05.pdf
National Institute of Child Health and Human Development. Families and Fragile X. Available at http://www.nichd.nih.gov/
Your genes your health: Fragile X syndrome. Available at http://www.ygyh.org/fragx/whatisit.htm
Resources for health professionals
GeneClinics. Availabe at www.geneclinics.org
GeneReviews. Availabe at www.genereviews.org (enter “Fragile X”)
Hagerman, R. J. (2001). Fragile X syndrome. In S. B. Cassidy & J. E. Allanson (Eds.), Management of genetic syndromes (pp. 165–183).
New York: Wiley-Liss.
Hagerman, R. J., & Hagerman, P. J. (2002). Fragile X syndrome: Diagnosis, treatment, and research (3rd Ed.). Baltimore, MD:
The Johns Hopkins University Press.
5. Make appropriate referrals for medical, edu-
cational, and mental health interventions and
discussions that are beyond the scope of ge-
netic counseling practice.
6. Provide contact information for support
groups and patient-appropriate resources, as
requested (Table III).
Analyze the pedigree and FMR1 DNA results
and provide genetic risk assessment for carrier sta-
tus and chance of having affected or carrier off-
spring. Inheritance principles for fragile X syndrome
1. All daughters of a male with a premutation
are obligate premutation carriers, whereas
none of his sons will inherit the mutation.
3. The risk for affected offspring in females car-
rying premutations varies with the length of
the repeat number (Table I).
4. Women with full mutations have a 50% risk
with each pregnancy to pass the full muta-
tion to the fetus. Although rare, there are re-
spring with reversions (decreases in the num-
(Loesch et al., 1995; Nolin et al., 1996).
5. Males with a full or mosaic mutation will
not pass it on to their sons and most likely
will pass on a premutation to their daugh-
males with full mutations have only premuta-
tions in their sperm, there are rare reports of
daughters with full mutations born to males
with full/mosaic mutations.
Informing Family Members
The diagnosis of fragile X syndrome can have
far-reaching genetic and emotional implications for
carriers as well as families who have been previously
for disclosing information about fragile X syndrome
262 McConkie-Rosell, Finucane, Cronister, Abrams, Bennett, and Pettersen
situations arise when key family members refuse to
relay information about fragile X syndrome to at-risk
Because of the difficulty frequently encountered
inform relatives as part of initial as well as follow-up
genetic counseling sessions. Genetic counselors can
assist families by identifying at-risk relatives in the
pedigree and reviewing strategies for broaching the
subject of diagnostic or carrier testing. Utilization of
a family network approach, which allows relatives to
initially be informed by a family member known to
them with follow-up by a genetic counselor, may be
helpful in facilitating informing relatives about their
genetic risks (McConkie-Rosell et al., 1995). Families
should be reassured that it is not their responsibil-
ity to provide in-depth genetic counseling or ensure
that other family members pursue testing. Families
with fragile X syndrome often find it helpful to have
an objective document, such as a succinct summary
letter with the genetic counselor’s contact informa-
tion, to give to other relatives at the time of disclo-
sure. As always, genetic counselors dealing with dif-
ferent branches within a family should be careful to
maintain confidentiality and avoid revealing clinical
and diagnostic information without the consent of
SPECIAL ISSUES REGARDING FMR1
Family History of Mental Retardation
of Unknown Etiology
tion of unknown etiology (e.g., an affected proband is
not available for testing) should be offered fragile X
carrier testing after counseling and education about
fragile X syndrome. Implications of results of carrier
testing, including available methods of prenatal diag-
nosis and possible results and their meaning should
also be discussed.
Women With a Positive Family History
All women with a family history of fragile X
syndrome who have been determined by pedigree
analysis to be at risk to be carriers should be offered
genetic counseling, including an informed consent
process, prior to carrier testing (Bennett et al., 2002;
McIntosh et al., 2000). The carrier testing process in
fragile X syndrome has been studied from the per-
spectives of at-risk women (McConkie-Rosell et al.,
drome (McConkie-Rosell et al., 1999). Findings from
this research can be used to develop genetic counsel-
The effect on self-concept related to the carrier
testing process has been studied in adult women at
50% risk for inheriting the fragile X mutation. While
overall self-concept was found to be stable, feelings
about self related to the implications of “being a car-
rier” were negatively affected. Five areas of concern
• implications of a positive carrier test for their
• possible expression of clinical features of frag-
ile X syndrome in themselves
• a heightened awareness of their genetic iden-
The decreased positive feelings about self and
the coping behaviors to manage them were present
in all the women when they were “at-risk” and per-
sisted in those women subsequently found to be mu-
tation carriers (McConkie-Rosell et al., 2001). These
findings suggest that pretest genetic counseling in-
terventions should include assessment of the coping
behaviors used to manage feelings related to “being
at risk” and facilitation of positive coping skills to
manage carrier test results. Coping resources include
physical resources (e.g., family finances, job skills, ed-
ucation, etc.), social and family support networks,
and psychological resources such as beliefs, cogni-
tive skills, problem solving abilities, and self-concept.
The adaptive coping behaviors identified in response
to genetic testing in adults include: pursuing hope,
constructing meaning, acquiring new knowledge and
coping methods, minimization, and perceived control
(Kessler et al., 1984; Marteau et al., 1997; McConkie-
Rosell et al., 2001; Shiloh et al., 1997).
Daughters of Males With Premutations
Test results for daughters of a male with a pre-
mutation should not be inferred from their father’s
Genetic Counseling for Fragile X Syndrome263
results. There is a possibility of misattributed pater-
nity or of gene reversion. Additionally, testing obli-
own genetic status.
Males With a Positive Family History
FMR1 testing in males has become more com-
plicated with the discovery of FXTAS. The newly de-
scribed clinical complication in premutation carriers
means that carrier testing may uncover a risk of un-
known magnitude for FXTAS later in life. Therefore,
presymptomatic testing concerns may apply. Addi-
tional epidemiological data are needed in order to
determine the age-related risk for FXTAS. Carrier
garding reproductive risk; and parental request for
testing secondary to educational or behavioral con-
cerns in a son. Carrier males may also be diagnosed
through prenatal testing. Each of these different cir-
cumstances has unique implications that affect the
risks and benefits of testing which should be consid-
ered in genetic counseling.
in the family, testing of the maternal grandparents
is often recommended in order to determine which
side of the family is at risk. The grandfathers of an
affected child are often close to the age of onset of
FXTAS or they may already be symptomatic. For
these men, DNA carrier testing may become diag-
may be appropriate.
Male relatives of an affected child may request
FMR1 testing for reproductive purposes because
Table IV. Risks and Benefits of Testing a Minor for Carrier Status
Potential adverse consequences of testing a minor
• Damage to the minor’s self-esteem.
• Distortion of the family’s perception of the child.
• Siblings may be treated differently depending on genetic status.
• Loss of future adult autonomy and confidentiality for the tested child.
• Adverse effects on the child’s capacity to form future relationships.
• Fear/guilt if person wants biological children.
• Discrimination (insurance, employment, education, choice of mate).
Potential benefits of testing a minor
• Resolution of the parent’s (and possibly the child’s) concerns about carrier status.
• Allows child and family time to adjust to test outcome and to develop coping behaviors.
• Genetic counseling can be tailored to the developmental stage of the child and anticipatory guidance provided
for future concerns.
• Child and parents can be informed of genetic risk prior to the occurrence of an unintended pregnancy.
• Allows for long-term integration of information regarding genetic status for family planning issues.
• Awareness of risk of premature ovarian failure allows decision-making regarding timing of future pregnancies.
males with premutations are at risk to have daugh-
ters who are premutation carriers. Therefore, genetic
counseling should include a discussion regarding the
issues of informing a daughter about her genetic risk
son. Careful consideration and discussion of the risks
and benefits of carrier testing to the male in question
should be the focus of the genetic counseling session
helping the family to determine when and how to in-
form about the genetic risk.
Fragile X carrier testing for children less than
18 years of age must be approached carefully, with
medical and emotional benefits to the child weighed
against potential harms (Table IV).
Research with parents of children with fragile X
syndrome (McConkie-Rosell et al., 1999) and with
obligate carriers of fragile X syndrome (McConkie-
Rosell et al., 1997) suggests that families are con-
could be carriers; how to weigh the potential risks
and benefits of carrier testing for their own family;
and how to help family members positively adapt to
vide this information to their children is complicated
and usually requires ongoing discussion. The genetic
counseling should focus on the adjustment to genetic
264 McConkie-Rosell, Finucane, Cronister, Abrams, Bennett, and Pettersen
risk status throughout the life cycle. How this infor-
will influence how the child adjusts to his/her genetic
risk and copes with that information as an adult.
Genetic counseling interventions should be tai-
lored to the developmental stage of the child
(McConkie-Rosell et al., 2002), and consideration
made to use a family approach in order to facili-
Rosell and Spiridigliozzi, 2004). Genetic counselors
need to be prepared to work with the parents to de-
to facilitate the discussions between parents and their
children. Topic areas to discuss in the development of
a plan include:
• How, when, and why parents want to talk with
their children about the genetic risk.
• Parents should be encouraged to think about
what “message” they are trying to convey to
is inherited, and what “being a carrier” means.
• Parents should be encouraged to take their
time in considering what they want to say and
be able to discuss genetic risk without over-
whelming the child with facts or emotion.
• Parents should also be aware that their chil-
dren’s needs and understanding may change
over time and discussions may need to be
repeated to address misunderstandings or
changes in their child(rens)’s needs. Genetic
ents potential times for follow-up counseling
sessions to address new issues.
Once a plan has been developed, genetic coun-
selors can facilitate discussions between parents and
• What have they been told and what do they
understand about fragile X syndrome, in gen-
• What do they understand about how fragile X
syndrome is inherited?
• What do they understand about their risk for
being a carrier? (If their status is known, e.g.,
a daughter of a carrier male, what does “being
a carrier” mean to them?)
• Are they interested in being tested?
In summary, there are both risks and benefits to
tential consequences should occur prior to decisions
about testing. It is important to adapt the above ge-
netic counseling approaches for minors identified as
premutation carriers through prenatal diagnosis and
for minor daughters who are assumed to be obligate
Counseling Issues for Carriers
Premature Ovarian Failure
Although the incidence of POF in females who
are carriers of the premutation has been found to be
about 20% for women under the age of 40 years, the
specific incidence in young women between the ages
of 20 and 35, who may be actively making reproduc-
tive plans or who are not yet ready to consider their
reproduction, has not yet been established. Carriers
be faced with altering their life plans related to child
bearing. Female carriers of the premutation should
be informed about the potential for reduced fertil-
ity. However, similar to counseling young girls with
Turner syndrome, care should be taken to present a
balanced picture of the potential for reduced fertility
in the context of life decisions and timing for repro-
duction (Sybert, 2001). Although surveillance for the
to recommend close medical follow-up for early signs
Family Planning Issues and Options
In addition to providing factual information re-
garding reproductive options, genetic counseling for
families managing the genetic risk for fragile X syn-
parental role (McConkie-Rosell and DeVellis, 2000).
Fundamental concepts of the parental role, includ-
ing how it is defined and fulfilled may need to be re-
inherent in the genetic risk. In this regard, the genetic
to fulfill the parental role (e.g., adoption, foster care,
remaining childless or no further children, parenting
a child with fragile X syndrome, and prenatal testing
Genetic Counseling for Fragile X Syndrome265
definition of what being a parent means and how im-
portant this role is to them.
Females With Full Mutations
Carrier testing may reveal that a female has ei-
with a family history of fragile X syndrome may have
the full mutation. The possibility of either the pre- or
full mutation and the implications of each should be
addressed prior to carrier testing.
Psychiatric and intellectual disabilities related
to fragile X mutations can also adversely affect the
genetic counseling process. Mental retardation, con-
ing in some women may limit the success of tradi-
tional genetic counseling approaches. Women with
cognitive and psychological impairments may benefit
than an education-based model of genetic counseling
(Finucane, 1998a, 1998b).
Premutations and Predisposition
to Psychological Issues
Psychological issues such as denial, anxiety,
depression, inability to cope, damage to self-esteem,
in sense of identity are potential reactions to any X-
Resta, 2000; Weil, 2000; Williams et al., 2000).
Complicating the reactions to the diagnosis or
carrier status itself can be one or more of the psycho-
logical components inherent to a proportion of pre-
mutation carriers (see the section on Clinical Presen-
and, if symptoms or signs present, appropriate refer-
rals to mental health professionals should be made.
Prenatal Diagnosis and Genetic Counseling
Prenatal diagnosis should be offered to women
identified as carriers of a pre- or full mutation. Males
identified as premutation carriers, and therefore at
risk to have premutation daughters, should also be
presented with the benefits and limitations of an in-
vasive procedure and the implications of prenatal re-
sults and be allowed to make the choice that is right
for them. As with other genetic conditions, it is the
role of the genetic counselor in the prenatal setting to
fully explain the implications of different test results,
including the range of possible outcomes for a female
fetus with a full mutation. The variable phenotype
among males and females with premutations should
also be emphasized. This information, as well as in-
formation regarding the benefits and limitations of
an invasive procedure, can facilitate patient decision-
making and help prepare patients who ultimately are
faced with a positive result.
Carrier Testing for Reasons Other Than
Fragile X Syndrome
Increasingly individuals are being referred for
fragile X testing for reasons other than a positive
family history of mental retardation. Such individuals
may include women with POF and individuals with
ataxia/tremor. Although there is currently no pub-
aware that the issues and responses to this informa-
perience, we postulate that areas in which differences
might be expected to occur include:
• Unexpected finding—For example: A woman
with POF may have previously been very fo-
cused on achieving a pregnancy and may have
been reassured that if she does become preg-
nant her risk is no different than any other
of fragile X syndrome might result in a signifi-
cant shift in this perception.
• Regret or anger—For example: If testing and
the diagnosis of fragile X syndrome occurred
after multiple expensive and/or invasive med-
ical procedures or multiple tries at pregnancy,
regret or anger may be expressed by the pa-
tient/family that testing was not considered
sooner in the diagnostic process. For both
FXTAS and POF different medical or life
ile X syndrome had been known earlier in the
• Implications for family—As noted previously,
once the diagnosis of fragile X syndrome has
been made there are significant implications
266 McConkie-Rosell, Finucane, Cronister, Abrams, Bennett, and Pettersen
ile X syndrome would be expected to shift the
focus from the individual as the “patient” to
now include the extended family.
Pregnant and Nonpregnant Women
Although currently not standard of care, offer-
ing fragile X carrier screening to pregnant women
or women considering pregnancy is becoming more
ily history of fragile X syndrome and be able to coun-
sel them prior to screening regarding the implications
allele sizes need counseling and education regarding
their particular results, the risks for expansion during
pregnancy, reproductive options and implications of
their result for other family members. Genetic coun-
selors are likely to receive referrals for women who
have had general population screening with results
showing premutation or intermediate allele sizes as
well as full mutations. Comprehensive education and
results in regard to family planning as well as risk to
other family members is essential.
Women With Intermediate-Sized Alleles
Population carrier screening for fragile X syn-
drome is likely to detect many women with
intermediate-sized alleles. Genetic counseling should
size alleles are not generally considered to be at risk
for clinical manifestations of either pre- or full muta-
tions. Some alleles in this range have been shown to
be unstable and to expand in subsequent generations,
phasize is that although guarantees cannot be given
for any allele size, to date, no female with fewer than
59 repeats has had a child with a full mutation. Some
prenatal diagnosis compared to the negligible risk of
having a fetus with a full mutation, need to be dis-
cussed at length with clients who are found to have
PATIENT AND PROFESSIONAL RESOURCES
firmed fragile X syndrome and individuals who are
confirmed mutation carriers can be offered patient-
quality resources appropriate for clients and families.
Health professionals caring for individuals with frag-
ile X syndrome or managing reproductive-related is-
sues in fragile X carriers may benefit from available
resources for health professionals (Table III).
Genetic counseling for fragile X syndrome is
inheritance, variable phenotype, and the implications
of these issues for families. Genetic counselors can
provide support with an emphasis on anticipatory
guidance for families throughout the life cycle—
from newborn screening, pediatric evaluations, re-
productive counseling, to evaluations of individuals
for FXTAS and POF. This important area of genetic
counselors have an important role in policy develop-
ment and implementation regarding FMR1 testing.
assistance with the literature review. We are grate-
ful to our reviewers Stephanie Sherman, Sally Nolin,
Amanda Bergner, Deby Burgess, and Robby Miller
for generously sharing their expertise, insight, and
time with us. We also thank the National Fragile X
Foundation for allowing us to use photographs from
their family files.
Allingham-Hawkins, D. J., Babul-Hirji, R., Chitayat, D., Holden,
J. J., Yang, K. T., Lee, C., et al. (1999). Fragile X premutation
is a significant risk factor for premature ovarian failure: The
International Collaborative POF in Fragile X study—
preliminary data. Am J Med Genet, 83, 322–325.
American College of Medical Genetics (1994). American College
of Medical Genetics Policy Statement. Fragile X syndrome:
diagnostic and carrier testing. Am J Med Genet, 53, 380–381.
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