tog_19.

qxd 4/6/11 3:29 AM Page 92

Review 2011;13:92–97 10.1576/toag.13.2.92.27652 http://onlinetog.org The Obstetrician & Gynaecologist

Review Fragile X syndrome:

an overview
Authors Katerina Bambang / Kay Metcalfe / William Newman / Tom McFarlane

Key content:
• Fragile X syndrome is the most common hereditary cause of learning difficulty
and the most common known cause of autism.
• It occurs as a result of mutations of the FMR-1 gene on the X chromosome and it
belongs to the family of trinucleotide-repeat disorders.
• The prevalence of the full genetic mutation is approximately 1 in 4000.
• The inheritance is X-linked dominant with reduced penetrance and variable
expressivity.
• Premutation carrier status is linked to fragile X tremor ataxia syndrome and
premature ovarian failure.

Learning objectives:
• To understand the clinical features and the basic genetics.
• To understand the nature and implications of premutation carrier status,
including the link with premature ovarian failure.
• To be aware of the complexities of counselling.
• To be aware of the UK policy on screening.

Ethical issues:
• There are issues about termination of pregnancy in relation to fragile X syndrome
and fragile X tremor ataxia syndrome.
• Carrier testing for fragile X syndrome has potential health implications for the
tested individual.

Keywords fragile X tremor ataxia syndrome / learning difficulty / preimplantation

genetic diagnosis / premature ovarian failure / screening
Please cite this article as: Bambang K, Metcalfe K, Newman W, McFarlane T. Fragile X syndrome: an overview. The Obstetrician & Gynaecologist 2011;13:92–97.

Author details
Katerina Bambang MBChB DFSRH
Clinical Research Fellow
Reproductive Sciences Section, Department of
Cancer Studies and Molecular Medicine,
University of Leicester, Robert Kilpatrick
Clinical Sciences Building, Leicester Royal
Infirmary, PO Box 65, Leicester LE2 7LX, UK
Email: KaterinaB@doctors.org.uk
(corresponding author)
Kay Metcalfe FRCP MD
Consultant Clinical Geneticist
University of Manchester Academic
Unit of Medical Genetics, St Mary’s Hospital,
Hathersage Road, Manchester M13 0JH,
UK
William Newman BSc (Hons) MBChB (Hons) MA
MRCP PhD
Consultant Clinical Geneticist
University of Manchester Academic Unit of
Medical Genetics, St Mary’s Hospital,
Hathersage Road, Manchester M13 0JH, UK
Tom McFarlane BSc FRCOG
Honorary Consultant Obstetrician; and
Gynaecologist
Stepping Hill Hospital, Poplar Grove, Hazel
Grove, Stockport SK2 7JE, UK

92 © 2011 Royal College of Obstetricians and Gynaecologists

tog_19.qxd 4/6/11 3:29 AM Page 93
The Obstetrician & Gynaecologist
Introduction
Fragile X syndrome (FXS) is the most common cause
of inherited learning difficulty and the most
common known genetic cause of autism. It is caused
by mutations of the FMR-1 (fragile X mental
retardation-1) gene on the X chromosome.The FMR-1
gene codes for fragile X mental retardation protein,
which is essential for normal brain development. The
phenotype associated with the full mutation occurs in
approximately 1 in 4000 men and 1 in 8000 women.1–3
Thecondition is more severe in men than in women.1
Genetic basis
Fragile X syndrome (FXS) is an unusual X-linked
dominant disorder. The condition was described by
Martin and Bell in 1943 and it was soon realised
that the inheritance had aspects that could not be
explained by normal mendelian theory. 4 The
mothers and daughters of a normal transmitting
male are obligate carriers and do not have learning
and developmental disability, while the grandsons
and granddaughters of the normal transmitting
male are much more likely to be affected with FXS
than the brothers of the normal transmitting male
(Figure 1). The FMR-1 gene was first identified in
1991 and can be present in different allelic sizes.5
These different sizes correlate with the phenotype
and risk of transmission (Table 1).
In the promoter region of the FMR-1 gene there
is a trinucleotide repeat, a section of DNA where
the nucleotide bases cytosine (C) and guanine (G)
are repeated in the sequence CGG-CGG-CGG,
etc.5,6 Mutations derive from increases in the
length of this repeat (expansion). The smallest
number of repeats known to have expanded
to the full mutation in the next generation
is 59.7
© 2011 Royal College of Obstetricians and Gynaecologists
2011;13:92–97 Review
Four allelic classes of the FMR-1 gene have been
defined (Table 1).8 The FMR-1 gene codes for fragile
X mental retardation protein. This is an RNA-
binding protein, which regulates local protein
synthesis. In the case of FXS, transcriptional
silencing occurs and no fragile X mental retardation
protein is produced, resulting in overproduction
of certain proteins in a variety of different cell
types but with a predilection for neurons.8
In the premutation, the FMR-1 gene is active. The
amount of fragile X mental retardation protein
produced is normal but there is overproduction of
mRNA, which is thought to create a toxic effect in
the cell.9 A similar effect has been demonstrated in
mouse models of myotonic dystrophy.10
Fragile X syndrome was one of the first
trinucleotide repeat disorders to be described;
others include Huntington disease and myotonic
dystrophy. In all of these conditions the gene
becomes unstable with larger numbers of repeats
and is prone to further expansion in the offspring,
causing them to have earlier onset or more severe
clinical effects.
Clinical features of fragile X
syndrome
Both men and women can be affected. Variable
expressivity causes the phenotype to range from
mild learning difficulties to severe intellectual
disability and autistic behaviour (Box 1).8 The
physical characteristics of the syndrome are often
quite subtle.
The first sign of the condition is usually delay in
achieving developmental milestones, particularly
motor and language development.11 More than
Figure 1
Example of a pedigree of FXS (note
increase in affected individuals in
later generations)
93
tog_19.qxd 4/6/11 3:29 AM Page 94

Review 2011;13:92–97 The Obstetrician & Gynaecologist

Table 1 Class Repeats Characteristics Phenotype

The four defined allelic classes of
Common 6–44 These are usually transmitted in the general population in a stable manner. Normal
the FMR-1 gene8
Intermediate 45–54 These give rise to the ‘grey zone’. Even the larger repeats are unlikely to expand enough Normal
to cause the disorder in the next generation.
Premutation 55–200 These are usually meiotically unstable and will often expand on transmission to the next Increased risk of
generation when passed on by a female. Those with more than 90 repeats almost always POF and FXTAS
expand to the full mutation in the next generation; however, the premutation is stable in
length when passed on by fathers.
Full mutation >200 FXS

FXTAS = fragile X tremor ataxia syndrome; POF = premature ovarian failure

Box 1 Developmental delay Behavioural features

Clinical characteristics of FXS
• Intellectual disability • Attention-deficit disorders
• Speech delay • Speech disturbance
• Coordination difficulties • Autistic features, e.g.
hand flapping, gaze
aversion, echolalia
• Hyperarousal or anxiety
Medical conditions Physical characteristics
• Epilepsy (20%) • Long face
• Mitral valve prolapse • Large, prominent ears
• Recurrent ear infections • High broad forehead
• Eye problems, e.g. strabismus • Large testicles after puberty
• Connective tissue
problems, e.g. flat feet,
high arched palate
• Scoliosis
25% of males with the syndrome meet the
diagnostic criteria for autism.12 Almost all affected
men have a degree of learning difficulty often
manifesting as difficulty with short-term memory,
executive function and visuospatial ability.1 By
contrast, women with the syndrome are often much
more mildly affected, possibly as a result of X
chromosome inactivation. They often have a
normal or borderline IQ but they appear to be at
higher risk of having problems such as depression,
mood lability and social anxiety compared with the
general population.14
Most affected men do not reproduce but it is not
known whether this is due to the severity of cognitive
difficulty or as a direct effect of the syndrome, which
is known to cause macro-orchidism after puberty.15
The spermatozoa of men with FXS contain the
premutation FMR-1 allele rather than the full
mutation. Women with the full mutation do not
have reduced reproductive potential and are at risk
of transmitting the full mutation to their children.16
In contrast, women with the premutation are at
increased risk of premature ovarian failure.
Fragile X tremor ataxia
syndrome
It was previously thought that premutation carriers
were unaffected, but there is now evidence to show
that this is not the case. Specifically, it appears that
there are two distinct conditions associated with
the premutation but not the full mutation: fragile X
tremor ataxia syndrome (FXTAS) and premature
ovarian failure.
Fragile X tremor ataxia syndrome is a
neurodegenerative disorder predominantly
occurring in male premutation carriers aged
>50 years; it was first reported in 2001.17 Five men
with the premutation were described who
had developed tremor and progressive
neurodegenerative disorders. Two of the men had
been professors, one had a PhD and one had been
an electrician. The occupation of the fifth was not
given. This shows that men with the premutation
do not have the intellectual impairment of those
with FXS. Indeed, they may be high-flyers in their
early lives. An erroneous diagnosis of Parkinson’s
disease had been made in one case.
The syndrome is characterised by progressive
cerebellar ataxia and intention tremor.18,19 There is
often progression to loss of sensation in the lower
extremities and autonomic dysfunction in the form
of impotence and faecal and urinary
incontinence.20 A significant number develop
dementia and this risk appears to increase with
increased allele length.21
Men affected by FXTAS have mild-to-moderate
brain atrophy on magnetic resonance imaging,
particularly in the cerebellum, involving the middle
cerebellar peduncles and the periventricular white
matter; and on post-mortem, intranuclear
inclusion bodies in astrocytes and neurons.22
The prevalence of FXTAS is unclear, but it may well
be that it is underdiagnosed. There are suggestions
that 30% of all male carriers will develop FXTAS
although many will not present until the eighth
decade.20 As the premutation is thought to occur in
as many as 1 in 813 men, it could affect a significant
percentage of the population.20
Female premutation carriers have a much lower
risk of FXTAS. However, a recent study23 suggests
that women with FMR-1 premutations are also
affected by FXTAS, with additional comorbidities,
including thyroid disease, hypertension, peripheral
neuropathy and fibromyalgia.
Fragile X premature ovarian
failure
Up to 26% of women who are carriers of the fragile
X premutation will experience premature ovarian
failure, compared with the general population risk

94 © 2011 Royal College of Obstetricians and Gynaecologists

tog_19.qxd 4/6/11 3:29 AM Page 95
The Obstetrician & Gynaecologist
of only 1%.8,15 A woman who has premature ovarian
failure has a 2–4% risk of being a carrier of the
fragile X premutation; this risk rises to 8–15% if
there is also a family history of premature ovarian
failure.24
There is a non-linear relationship between the
number of trinucleotide repeat sequences and the
risk of premature ovarian failure. The highest risk
occurs with repeats of 59–99.25 The risk plateaus or
even decreases with repeat sizes of >100. Women
with the full mutation do not have an increased risk
of premature ovarian failure.25
The mechanism behind the impaired ovarian
function is unknown. Theories include a decreased
number of ovarian follicles in the initial pool or an
accelerated rate of follicular atresia.
The prevalence of the premutation in women is
thought to be approximately 1 in 259, although two
studies26,27 have suggested that it may be as high as
1 in 113 to 1 in 152.26–28 This makes fragile X-linked
premature ovarian failure potentially a relatively
common condition.
A cross-sectional survey29 of women from families
with a history of FXS demonstrated that
premutation carriers reported irregular menses and
shorter cycles more frequently than non-carriers.
Various measures suggestive of ovarian
insufficiency have been documented in women
with the premutation who are still menstruating.
These include elevated follicle-stimulating
hormone levels throughout the menstrual cycle, as
well as elevated serum markers such as inhibin A,
inhibin B and progesterone.30
More recently, research has shown anti-Müllerian
hormone to be abnormally high in premutation
carriers prior to the menopause.31 This could
potentially be developed as a prognostic marker for
predicting ovarian decline at a much earlier stage.
There is no validated test for assessing the risk of
altered ovarian function in asymptomatic women
who carry the premutation. Women must be
informed that there is still a 5–10% chance of
conception after premature ovarian failure.32
Fragile X syndrome and
screening
There are significant implications to testing positive
both for the full FMR-1 mutation and the
premutation. A man with the full mutation will
usually have problems such as learning difficulties
or autism that have already been noted. Testing in
this context is considered as diagnostic, conferring
an accurate diagnosis, removing the need for
further unnecessary diagnostic investigations and
© 2011 Royal College of Obstetricians and Gynaecologists
2011;13:92–97 Review
introducing the potential for future treatment
developments. Importantly, it also offers the
possibility of screening for the premutation in
relatives.
A woman with the full FMR-1 mutation has the
potential to reproduce and transmit the mutation
to her offspring. Fifty percent of male offspring
would inherit the full mutation and have FXS,
whereas 50% of female offspring would also inherit
the full mutation but only half of them would be
expected to have the clinical features of FXS.
Identification of an FMR-1 mutation or
premutation would allow counselling about
reproductive options, which might include
prenatal diagnosis or preimplantation genetic
diagnosis. Many individuals carrying an FMR-1
premutation or full mutation do not opt for
prenatal diagnosis.
Screening for premutations in males should be
preceded by adequate counselling, as identification
of a premutation would indicate a significant risk of
being affected by a late-onset neurodegenerative
disease. However, depending on the mother’s
carrier status, it is possible that testing would give
a 50:50 chance of a negative result and the potential
relief of being at no risk of the disease or of passing
it on to the next generation.
Screening for the premutation in women poses
different dilemmas. Fragile X tremor ataxia
syndrome is less common and less debilitating in
women than in men.33 Identification of a
premutation indicates a higher risk of premature
ovarian failure, therefore, women may use this
knowledge to secure their fertility by having their
children while still young or by using techniques
such as oocyte storage. Knowledge of premutation
status also allows discussion of reproductive
options, including prenatal diagnosis and
preimplantation genetic diagnosis.
A recent health technology assessment by the
National Health Service34 found that both antenatal
and cascade screening (testing within families of
affected individuals) are feasible and acceptable but
are not currently incorporated into routine
practice. Various strategies for screening have been
considered, including routine antenatal screening,
preconception testing of all women and cascade
screening. There is no research evidence as to the
efficacy of the different strategies.
Fetal sex can be determined by testing cell-free fetal
DNA in maternal blood, usually at around 9 weeks
of gestation. This will facilitate decisions about
proceeding to prenatal diagnosis. The FMR-1 status
of the fetus can be determined prenatally by
chorionic villus biopsy or amniocentesis.
95
tog_19.qxd 4/6/11 3:29 AM Page 96
Review 2011;13:92–97
The diagnosis of a premutation carrier fetus raises
difficult ethical questions about termination of
pregnancy: does a 30% risk of FXTAS in middle age
in a male fetus constitute grounds for termination?
Does the risk of premature ovarian failure or
FTXAS in a female offspring with a premutation
constitute appropriate grounds for consideration of
termination? Furthermore, it is important to note
that only 50% of females with the FMR-1 full
mutation will have a learning disability and the
decision on whether or not to terminate a
potentially healthy fetus is challenging.
Preimplantation genetic diagnosis can potentially
be used to allow the selection of embryos without
the mutation; however, the molecular techniques
applied do not allow distinction between the pre-
and full FMR-1 mutations. Furthermore, a
potential difficulty is that women with the
premutation often have elevated baseline follicle-
stimulating hormone levels and may not respond
well to gonadotrophin stimulation, limiting the
number of embryos available for selection.25
Australia, Belgium, France and the Netherlands
have licensed preimplantation genetic diagnosis
for FXS; it has also recently been approved by the
Human Fertilisation and Embryology Authority.
The European Society of Human Reproduction
and Embryology has suggested that any woman
presenting for infertility investigations should be
screened for FXS, but they have not given any
specific guidance.35 This was supported by the
American College of Medical Genetics, who also
advised that any woman presenting with elevated
follicle-stimulating hormone levels, a family
history of premature ovarian failure or relatives
with undiagnosed learning difficulty should be
screened.6
Conclusion
Fragile X syndrome is common and has a significant
impact on the health service. All at-risk and affected
individuals should be offered genetic counselling to
discuss the many complex aspects of the condition
and the implications for themselves and family
members. Genetic screening for the FMR-1
premutation should be accompanied by counselling
regarding the implications of the diagnosis for the
individual, their offspring and relatives, as well as
the management options available. There are
concerns that the current resources available are
limited for coping with this demand.25 More work is
needed to determine the efficacy of screening
strategies and to assess the current capacity of the
UK National Health Service to cope.
Cell-free fetal DNA in maternal blood, prenatal
diagnosis and preimplantation genetic diagnosis
are all available to clarify the risks in offspring.
These options should be discussed with at-risk
96
The Obstetrician & Gynaecologist
individuals and adequate provision made to meet
the family needs. See Websites section for further
information.
Websites
The National Fragile X Foundation (in the USA)
[www.fragilex.org]
The Fragile X Society (in the UK)
[www.fragilex.org.uk]
References
1 Crawford DC, Acuna JM, Sherman SL. FMR1 and the fragile X syndrome:
human genome epidemiology review. Genet Med 2001;3:359–71.
doi:10.1097/00125817-200109000-00006
2 Turner G, Webb T, Wake S, Robinson H. Prevalence of fragile X syndrome.
Am J Med Genet 1996;64:196–7. doi:10.1002/(SICI)1096-
8628(19960712)64:1-3.0.CO;2-G
3 Morton JE, Bundey S, Webb TP, Macdonald F, Rindl PM, Bullock S. Fragile
X syndrome is less common than previously estimated. J Med Genet
1997;34:1–5. doi:10.1136/jmg.34.1.1
4 Martin JP, Bell J. A pedigree of mental defect showing sex linkage. J
Neurol Psychiatry 1943;6:154–7. doi:10.1136/jnnp.6.3-4.154
5 Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, et al. Variation
of the CGG repeat at the fragile X site results in genetic instability:
resolution of the Sherman paradox. Cell 1991;67:1047–58.
6 Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and
carrier testing. Genet Med 2005;7:584–7. doi:10.1097/01.GIM.
0000182468.22666.dd
7 Hagerman PJ, Hagerman RJ. The fragile-X pre-mutation: a maturing
perspective. Am J Hum Genet 2004;74:805–16. doi:10.1086/386296
8 Garber KB, Visootsak J, Warren ST. Fragile X syndrome. Eur J Hum Genet
2008;16:666–72. doi:10.1038/ejhg.2008.61
9 Nolin SL, Brown WT, Glicksman A, Houck GE Jr, Gargano AD, Sullivan A,
et al. Expansion of the fragile X CGG repeat in females with premutation
or intermediate alleles. Am J Hum Genet 2003;72:454–64.
doi:10.1086/367713
10 Kenneson A, Zhang F, Hagedorn CH, Warren ST. Reduced FMRP and
increased FMR1 transcription is proportionally associated with CGG
repeat number in intermediate length and pre-mutation carriers. Hum Mol
Genet 2001;10:1449–54. doi:10.1093/hmg/10.14.1449
11 Maes B, Fryns JP, Ghesquiere P, Borghgraef M. Phenotypic checklist to
screen for fragile X syndrome in people with mental retardation. Ment
Retard 2000;38:207–15. doi:10.1352/0047-6765(2000)038-2.0.CO;2
12 Clifford S, Dissanayake C, Bui QM, Huggins R, Taylor AK, Loesch DZ.
Autism spectrum phenotype in males and females with fragile X full
mutation and premutation. J Aut Dev Dis 2007;37:738–47.
doi:10.1007/s10803-006-0205-z
13 Crawford DC, Acuna JM, Sherman SL. FMR1 and the fragile X syndrome.
Genet Med 2001;3:359–71. doi:10.1097/00125817-200109000-00006
14 Freund LS, Reiss AL, Abrams MT. Psychiatric disorders associated with
fragile X in the young female. Pediatrics 1993;91:321–9.
15 Ryan MJ, Aydin A. Fragile X and reproduction. Curr Opin Obstet Gynaecol
2008;20:216–20. doi:10.1097/GCO.0b013e3282fe7254
16 Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt
CK, Rebar RW, et al. The FMR-1 premutation and reproduction. Fertil Steril
2007;87:456–65. doi:10.1016/j.fertnstert.2006.09.004
17 Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, et al.
Intention tremor, parkinsonism, and generalized brain atrophy in male
carriers of fragile X. Neurology 2001;57:127–30.
18 Berry-Kravis E, Lewin F, Wuu J, Leehey M, Hagerman R, Hagerman P,
Goetz CG. Tremor and ataxia in adult fragile X premutation carriers:
blinded videotape evaluation. Ann Neurol 2003;53:616–23.
doi:10.1002/ana.10522
19 Hagerman PJ, Hagerman RJ. Fragile X associated tremor/ataxia
syndrome (FXTAS). Ment Retard Dev Disabil Res Rev 2004;10:25–30.
doi:10.1002/mrdd.20005
20 Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg
JA, et al. Penetrance of the fragile X associated tremor ataxia syndrome
(FXTAS) in a premutation carrier population. JAMA 2004;291:460–9.
21 Sevin M, Kutalik Z, Bergmann S, Vercelletto M, Renou P, Lamy E, et al. The
penetrance of marked cognitive impairment in older male carriers of the
FMR1 gene permutation. J Med Genet 2009;46:818–824.
22 Brunberg JA, Jacquemont S, Hagerman RJ, Berry-Kravis EM, Grigsby J,
Leehey MA, et al. Fragile X premutation carriers: characteristic MR
imaging findings of adult male patients with progressive cerebellar and
cognitive dysfunction. Am J Neuroradiol 2002;23:1757–66.
23 Coffey SM, Cook K, Tartaglia N, Tassone F, Nguyen DV, Pan R. Expanded
clinical phenotype of women with the FMR1 premutation. Am J Med
Genet 2008;146A:1009–16. doi:10.1002/ajmg.a.32060
24 McDonough PG. Selected enquiries into the causation of premature
ovarian failure. Hum Fertil 2003;6:130–6.
doi:10.1080/1464770312331369393
25 Sullivan AK, Marcus M, Epstein MP, Allen EG, Anido AE, Paquin JJ, et al.
Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod
2005;20:402–12. doi:10.1093/humrep/deh635
© 2011 Royal College of Obstetricians and Gynaecologists
tog_19.qxd 4/6/11 3:29 AM Page 97
The Obstetrician & Gynaecologist
26 Hagerman RJ, Hagerman PJ. The fragile X premutation: into the
phenotypic fold. Curr Opin Genet Dev 2002;12:278–83.
doi:10.1016/S0959-437X(02)00299-X
27 Toledano-Alhadef H, Basel-Vanagaite L, Magal N, Davidov B, Ehrlich S,
DrasinoverV, et al. Fragile-X carrier screening and the prevalence of
premutation and full-mutation carriers in Israel. Am J Hum Genet
2001;69:351–60. doi:10.1086/321974
28 Pesso R, Berkenstadt M, Cuckle H, Gak E, Peleg L, Frydman M, et al.
Screening for fragile X syndrome in women of reproductive age. Prenat
Diagn 2000;20:611–14. doi:10.1002/1097-0223(200008)20:8<611::AID-
PD881>3.0.CO;2-M
29 Hunter JE, Epstein MP, Tinker SW, Charen KH, Sherman SL. Fragile X-
associated premature ovarian insufficiency: evidence for additional
genetic contributions to severity. Genet Epidemiol 2008;32:553–9.
doi:10.1002/gepi.20329
30 Welt CK, Smith PC, Taylor AE. Evidence of early ovarian aging in fragile X
premutation carriers. J Clin Endocrinol Metab 2004;89:4569–74.
doi:10.1210/jc.2004-0347
© 2011 Royal College of Obstetricians and Gynaecologists
2011;13:92–97 Review
31 Rohr J, Allen EG, Charen K, Giles J, He W, Dominguez C, Sherman SL.
Anti-Müllerian hormone indicates early ovarian decline in fragile X mental
retardation (FMR1) premutation carriers: a preliminary study. Hum
Reprod 2008;23:1220–5. doi:10.1093/humrep/den050
32 Van Kasteren YM, Shoemaker J. Premature ovarian failure: a systematic
review on therapeutic intervention to restore ovarian function and achieve
pregnancy. Hum Reprod Update 1999;5:483–92.
doi:10.1093/humupd/5.5.483
33 Hagerman RJ, Leavitt BR, Farzin F, Jacquemont S, Greco CM, Brunberg
JA. Fragile-X-associated tremor/ataxia syndrome in females with the
FMR-1 mutation. Am J Hum Genet 2004;74:1051–6. doi:10.1086/420700
34 Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A. Screening for
fragile X syndrome: a literature review and modelling study. Health
Technol Assessm 2003;7:1–59.
35 Soini S, Ibarreta D, Anastasiadou V, Ayme S, Braga S, Cornel M, et al. on
behalf of ESHG and ESHRE. The interface between assisted reproductive
technologies and genetics: technical, social, ethical and legal issues. Eur
J Hum Genet 2006;14:588–645. doi:10.1038/sj.ejhg.5201598
97