Fragile X associated primary ovarian insufficiency Fragile X associated decreased ovarian reserve Fragile X syndrome and reproduction evidence based Dr.Anu.M - Mch Resident - Department of Reproductive Medicine and Surgery

1. FRAGILE X AND
INFERTILITY

2. OBJECTIVES

3. Fragile X syndrome
Fragile X premutation-associated conditions
Fragile-X associated Primary Ovarian Insufficiency - FXPOI
Fragile-X associated diminished ovarian reserve - FXDOR
Potential mechanisms leading to FXDOR and FXPOI
Counselling, preventative measures and interventions

4. What is Fragile X Syndrome?

5. FRAGILE X SYNDROME (FXS)
Most common cause of
inherited intellectual
disability in males
Leading single-gene
defect associated with
autism spectrum
disorder(5%)
Fragile X mental
retardation (FMR1)
gene  FMRP
Near end of long arm
of X chromosome,
locus Xq27.3
CGG(Cytosine-Guanine-
Guanine) trinucleotide
repeat within the 5’
untranslated region of
exon 1 of FMR1 gene
Characteristic fragility
in that locus observed
during karyotyping
(Sutherland and Ashforth, 1979)

7. FMRP
Selective RNA binding protein- forms a
messenger ribonucleoprotein complex,
associates itself with polyribosomes 
involved in translational control – Protein
synthesis regulation at level of dendritic
spine
Brain , testis, ovaries,
liver, lungs, kidney,
spinal cord, GI tract
Nucleocytoplasmic shuttling of
mRNA, dendritic mRNA localization,
regulation of synaptic protein
synthesis  synaptic plasticity

8. 4 ALLELIC FORMS

9. The most common repeat length is 29 or 30 CGG repeats
No. of CGG repeats Interpretation
5 to ≤44 Normal unaffected gene
≥45 to ≤54 Intermediate/gray zone  CGG repeat instability in the
gene transmission to the next generation (Nolin et al., 1996)
≥55 to ≤ 200 Premutation(PM)
>200 Full mutation(FM)  FXS

10. Full mutation – Female
carriers
random inactivation of
one X chromosome
mRNA can be
transcribed from the
normal but not the
mutated-methylated
allele
lower but measurable
FMRP levels
Premutation
Increased level of FMR1
gene transcription but
decreased translation
Low to normal levels of
FMRP
↑FMR1 mRNA(with
↑CGG repeats)
Full mutation – FXS in males
FMR1 allele affected by DNA
hypermethylation of
promotor and CGG repeat
region
Inactivation-
transcriptional silencing
No FMRP

11. FXS  Males more severely affected
Distinctive facial
features- develop
over time – mean
age of △-3years
Phenotypic
features often are
not apparent until
later in childhood
Spectrum of
cognitive
phenotype
Behavioral
phenotype
Reproduction
Elongated face Enlarged testicles
(macroorchidism-
95%)
Developmental
delay
ADHD Fertile and capable of
reproduction (Hagerman et al.
2001)
Prominent
forehead
Connective tissue
disorders :
Hyperflexible joints,
hyperextensible
fingers, thumbs,
wrists
Intellectual and
learning disabilities
Speech and
language delay
Most affected males don’t
reproduce, presumably due to
severity of intellectual disability
(Crawford et al., 2001)
Large protruding
ears
Macrocephaly Anxiety
Majority –
intellectual disable
Autism spectrum
disorders
Strabismus
High arched palate
Occasional cleft
palate

12. Severity of intellectual disability IQ
Profound <20
Moderate (Most common) 40-54
Mild 50-70
Males can
reproduce
15% of males, who have an
IQ at ≥70

13. FXS in female
Subtle phenotype
Difficult to
diagnose based
on clinical
features alone
50% some
characteristic
physical features
Final phenotype depends
upon ACTIVATION RATIO-
ratio of cells with the
normal allele present on
active X chromosome
↑AR correspond to
↑ FMRP expression
levels produced by
the normal FMR1
allele
Intellectual impairment is
usually less severe than
observed- 70% have borderline
IQ or lower – executive
function defects
At risk of transmitting
a FM to their progeny
Women with a PM
have an increased risk
of FXPOI compared to
that of FM patients
(Allingham-Hawkins et al., 1999)

14. PREVALENCE

15. SEX PREMUTATION FULL MUTATION
Females 1:150-1:300 (Hunter et al., 2014) 1:8400 (Pesso et al., 2000)
Males 1:400-1:850(Hunter et al., 2014) 1:4000 (Turner et al., 1996)
2.4% with intellectual disability
Racial/ethnic variations
Columbia, Isreal 1:100 females(Seltzer et al., 2012)
Japan 1:1674 females(Hunter et al.,2014)
Tamil Nadu 1:353 females (Indumathi N et al., 2012)
PREVALENCE
Asian - 7.94% of POI
Western – 13.8%
(Anser et al., 2019)
Frequency of women with the premutation attending reproductive endocrinology clinics for
infertility is significantly increased compared with the carrier frequency expected in
the general population – 3%

16. Fragile-X premutation associated conditions

17. Fragile-X-associated tremor/ataxia
syndrome (FXTAS) – adult-onset
neurological disorder affecting
primarily males
Fragile-X-associated primary
ovarian insufficiency (FXPOI)
Fragile-X-associated diminished
ovarian reserve (FXDOR)
PM associated
disorders, distinct
from FXS
Incomplete
penetrance
There is no evidence to support an association between high
normal and intermediate range (45–54 repeats) FMR1 alleles
with a risk of FXPOI.

18. FXTAS
Late onset
Progressive
Intention tremor,
ataxia
Progressive
cognitive and
behavioral
deterioration
Memory loss
Anxiety Reclusive behavior
Executive function
deficits
Dementia
Phenotype gets
more defined and
prevalent with age
Premutation
repeat length
40% of men and 16% female
with PM (unfavourable X-
chromosome inactivation),
over age 50

19. Other characteristic phenotypes associated with PM
Attention deficit
hyperactivity
disorder (ADHD)
Autism spectrum
disorders
Intellectual
disability
Childhood
seizures
Adult onset
psychiatric
conditions
Migraine
headaches
Immune-mediated
disorders, mainly
thyroid
Hypertension
Fibromyalgia
Chronic muscle
pain

20. European Fragile X Network (EFXN),May 2020
Fragile X–associated neuropsychiatric disorders (FXAND)

21. Primary Ovarian Insufficiency

22. Normal ovarian function – continuous process
Fetal life  primordial germ cells (PGC) formation,
proliferation and migration, & development of follicular
units
Neonatal and adult life  steady follicular loss or atresia
Menopause  physiologic insufficiency of the ovary
Susceptible to various intrinsic
and extrinsic factors  impair
normal formation/function
Genetic defects
Smoking
Endometriosis
Chemotherapy
Radiotherapy
Ovarian surgery

23. POI
Extreme spectrum of an impaired
ovarian function
Coined by Albright et al., 1942 – 11 young women 
primary defect was within the ovary
Serum estrogen Amenorrhea FSH
Not a mandatory criterion for
diagnosis - <50pg/ml indicates
hypoestrogenism
Phenotypic extent of POI > 25 IU/L on 2 occasions
>4 weeks apart
Many, but not all, women with POI
develop symptoms of estrogen
deficiency
Broadened inclusion criteria – any cycle
irregularities
Hot flashes, vaginal dryness, sleep
disturbances
Oligomenorrhea, polymenorrhea,
menometrorrhagia, DUB, amenorrhea-
primary/secondary
Intermittent ovarian function Oligo/amenorrhea for atleast 4 months
Some women experience hot flashes
despite continued regular menses
Clinical syndrome
defined by loss of
ovarian activity before
the age of 40

25. POI
Multifactorial disease
90% - idiopathic
10% - identifiable etiology
FMR1 PM – one of the most
common single-gene mutation
causes of POI in women with a
normal karyotype  FXPOI
Other single-gene mutations: Bone
morphogenetic protein 15 (BMP-15),
Diaphanous homolog 2 (DIAPH2) and
Inhibin alpha subunit (INHA)

26. POI ≠ MENOPAUSE
Ovarian function can still be
present  unpredictable,
intermittent
50% POI  retain
intermittent ovarian
function for many years
spontaneous follicular
development, menstruation
5-10% POI can conceive (van
Kasteren and Schoemaker, 1999) and
deliver a child without any
medical intervention, even years
after diagnosis was established
12.6% FXPOI conceived
spontaneously after
diagnosis ranging upto 12
years (Hipp et al., 2016)
20% FMR1 PM  FXPOI
(20 fold increase)
3% before 29 years
1.4% prior to 18 years
FMR1 PM  2-6%
idiopathic sporadic POI, and
14% familial POI

27. POI – 2 main mechanisms
Inadequate formation of
the follicular pool in utero
Abnormally extensive or
fast depletion of the
follicular pool via atresia
during post-natal (neonatal,
childhood and adult) life
POI would be preceded by
some degree of DOR
Continuum of compromised ovarian function over time(normal ovarian function followed by
an early menopause)
Occult stage –
normal FSH, regular
mensus, but
reduced fecundity
Biochemical
manifestation(↑FSH,
regular mensus,
reduced fertility)
Overt ovarian
insufficiency –
irregular / absent
menses + ↑FSH

28. Consequences of POI
Increased risk for low
BMD
Earlier onset
osteoporosis, bone
fractures
Impaired endothelial
function
Untreated POI –
reduced life expectancy
- cardiovascular disease
Significant negative
impact on psychological
well being and quality
of life
Neuroprotectant 
possible detrimental
effect on cognitive
function , increased risk
of Alzheimer disease

29. FXPOI

30. Ovarian dysfunction in PM carriers
No apparent
difference in age of
menarche (Allen et al.,2007)
Reproductive span
reduced
First clinical hint  3%
adolescents with PM – non-
specific menstrual cycle
irregularities(De Caro et al., 2008)
Irregular menses
more often than non-
carriers
PM carriers have shorter
menstrual cycles in
comparison to age-
matched
women(↓follicular phase)
FXDOR precedes
FXPOI by 10 or more
years  impaired
fertility before age 35

31. Hormonal profile alterations
FSH from pituitary,
stimulates the growth and
recruitment of immature
ovarian follicles
Ovarian aging, diminished
number of follicles 
↓inhibin  ↓ FSH negative
feedback  ↑FSH release
PM carriers demonstrate
significantly higher follicular
phase FSH(D 1–10) when
compared to healthy,age-
matched women (Murray et al.,
1999)
↑FSH also in luteal phase
↓ Inhibin A, Inhibin B 
impaired follicular and
luteal ovarian function

33. AMH more sensitive than FSH
in identifying an early decline
in ovarian function among
PM carriers (Rohr et al.,2008)
Subtle decrease in AMH, as
early as 18 years(Normal
FSH) low ovarian reserve
continuous deterioration of
ovarian function
For all women, AMH was found to decrease by 10 % per year.
The added effect of carrying a premutation decreased AMH levels by 54 % (Spath et al., 2011)

34. Elevated expression of AMH and FSH receptor might initially accelerate follicular recruitment, but later it evokes a
vicious cycle causing secondary damage to the ovarian reserve and resulting in POI.

35. FXPOI
Increased rate of infertility
(46.6% of FXPOI)
Despite early DOR, no increase in
miscarriage rate/chromosomal
abnormalities due to maternal age-
related chromosomal nondisjunction
in the offspring
Oocyte competence
continues to be related to
chronological age  only
relative drop in follicle
number
Menopause, on average, 5
years earlier
Among females with POI
and a normal karyotype, 6%
have a premutation in
FMR1 gene

36. Correlation between Number of Repeats and Ovarian Function
PM CGG repeat (55-200) Non-linear association
59-99  Risk increases with increased PM repeats
Lower response to COH (Bibi et al.,2010)
Fewer eggs retrieved than controls (Elizur et al.,2014)
Decreased fertilization rate
80-99 Greater risk of FXPOI (Ennis et al.,2006)
>100 Risk declines (Sullivan et al.,2005)
The official statement of the ACMG is that a repeat length lower than 45 is not
associated with an abnormal phenotype (Monaghan et al., 2013).

38. 70–100 CGG repeats  at the highest risk for FXPOI
<65, >120 repeats did not have a significantly increased risk

39. FXDOR

40. DOR
Ovarian reserve defines the women’s reproductive potential as a function of number and
quality of her remaining oocytes (Practice Committee of the American Society for Reproductive Medicine, 2015).
POI – Overt phenotype-several years to develop-unless secondary to
oophorectomy/chemo/radiotherapy
DOR-Subtle- regular menses but a reduced quantity of ovarian follicles
Limited response to ovarian stimulation and reduced fecundity (Committee on Gynecologic Practice, 2015)
Evidence of DOR does not necessarily equate with the inability to conceive (Practice Committee of the
American Society for Reproductive Medicine,2015).

41. Definition of FXDOR
PM carriers with
reduced ovarian
reserve
Clinically appropriate term
 Continuous
deterioration along with its
fluctuant nature
DOR might/might
not lead to overt
FXPOI
Biochemical or Occult
phase of ovarian
insufficiency (Welt, 2008)
 fluctuating FSH levels
Diagnosis of exclusion, after excluding all
other known causes of infertility(male factor,
endometriosis, mechanical factor) in a
woman carrying a PM allele, with regular
menses regardless to the levels of ovarian
markers, younger than 40 years
No established gonadotrophin concentration cutoff
to suggest the initiation of ovarian insufficiency
(Panay and Kalu, 2009), most probably due to the
fluctuant and reversible nature of the ovarian
function.

42. FXDOR
Asymptomatic – subtle – possibly subfertility/infertility- prevalence
undetermined (unlike FXPOI – alarming menstrual irregularities)
SCREENING MERITS CONSIDERATION IN WOMEN WITH DOR

43. Recent Scientific Findings Proposing Possible
Mechanisms Of Ovarian Dysfunction In PM Carriers

44. Maintenance of PGC require FMRP
During embryonic
development at 6–8 weeks,
germ cells begin to divide
rapidly
By 16–20 weeks, fetal ovaries
contain 6–7 million follicles,
reaching its peak
Human FMRP is expressed in
PGC surrounded by FMRP-
negative pregranulosa and
interstitial cells (Rifé et al., 2004)
Strong inhibition of FMRP
translation of mutant FMR1 mRNA
 ↓FMRP with ↑Repeat length 
affect volume of follicular pool
increase in FMR1
toxic mRNA
aggravates the
ovarian dysfunction
FMRP is required for
preservation of
germline stem cells
(GSCs) in the
ovaries(Yang 2007)
Premutation RNA causes a reduction in the number of growing follicles acting through Akt and
mTOR

45. Gonadal impairment consequent to FMR1 premutation

46. ↑Mutant FMR1 mRNA with CGG repeats
Formation of secondary RNA structures - intramolecular
hairpins, R-loop formation(DNA-RNA hybrid)
Proteins bind to these non-canonical RNA structures
RNA-protein aggregates in the granulosa cells
Loss of function of these RNA binding proteins
compromise cell integrity  early follicular delay
Increased mRNA levels in granulosa cells of PM women
During normal
folliculogenesis,
FMRP is
predominantly
expressed in
granulosa cells, in
all stages of ovarian
follicular
development

47. RNA-binding proteins
hnRNP A2
Purα
Lamina A/C
miRNA biogenesis complex
Drosha/DGCR
Sam68
SAM68  regulate the
splicing of mRNA of FSH
and LH receptors (Bianchi et al.,
2010)
Altered splicing of these
proteins could lead to
ovarian resistance to FSH
and LH at the receptor level.

48. Abnormal stromal cells 
follicular atresia  early
decay of ovarian pool
Ubiquitin-positive
intranuclear inclusion in
ovarian stromal cells, not
in follicles per se

49. Correlation between Number of Repeats and Ovarian Function
PM CGG repeat (55-200) Non-linear association
59-99 Risk increases with increased PM repeats
>100 Risk declines (Sullivan et al.,2005)
↑ FMR1mRNA with ↑ PM repeat
length
Due to skewed X-inactivation,
mRNA levels tend to normalize in
females when the number of CGG
repeats increases >100 (Garcia-Alegria et
al., 2007)

50. Long noncoding (lnc) RNAs
novel lncRNAs,
named FMR4 and
FMR6 - originate
from the FMR1 gene
locus
FMR4 expression
downregulated in brain
tissue from FXS
patients and
upregulated in PM
carriers.
Regulate FMR1
stability, splicing,
subcellular
localization, and
translational
efficiency
Both FMR1 mRNA
and FMR6 lncRNA
showed increased
accumulation in GCs
from PM carriers
Pastori C, Wahlestedt C (2012)

51. Pattern of Inheritance

52. Pattern of inheritance
FM evolves during an
intergenerational,
multistep process –
ANTICIPATION (Pembrey et al., 1985)
Both PM, FM within
FMR1 gene are
inherited in an X-linked
dominant fashion

53. Female PM carriers
transmit it to 50% of
their offspring(both
male and female
progeny)
Males transmit PM
to all of their
daughters and
none of their sons
Meiotic instability of the repeat sequence

54. Pattern of inheritance
Number of CGG repeats within maternal
permutated allele may undergo expansion
During
oogenesis (Malter et
al., 1997)
During postzygotic mitoses
in embryo (Wohrle et al., 1993)

55. Protective factors in inheritance of PM from father
Only maternally
inherited PM can
expand into a FM in
the next generation
PM as well as FM
fathers can transmit
only a PM to their
daughters(Fisch et al., 1995)
Paternally inherited
PM does not expand to
same extent as one
inherited from mother
and can frequently
contract
40% daughters of male PM
carriers have PM with a lower
number of CGG repeats than
their fathers Vs 2% of daughters
whose PM are shorter than their
carrier mothers

56. Transmission from
father expands by
relatively fewer repeats
compared to
transmission from
mother (Fisch et al., 1995)
Reason : Sequences
with a high number of
CGG repeats are highly
unstable in the
developing sperm and
jeopardize their
survival
Only PM-size alleles
found in spermatozoa
of PM, as well as FM
males (Reyniers et al.,1993)
Protective factors in inheritance of PM from father

57. Mentally disabled female
child who inherited both a
PM as well as a FM from her
mosaic father
Father’s peripheral blood
cells demonstrated
mosaicism, both
permutated and full
mutated FMR1 allele were
present
His spermatozoa only
contained the permutated
allele
Expansion to a FM must
have occurred post-
zygotically.

58. Number of CGG repeats within maternal PM allele is in direct
correlation with probability of expanding into a FM in the offspring
(Nolin et al., 2011)
Maternal allele with 55-59 CGG
repeats
3.7% risk of expanding into a FM in
the next generation
≥100 repeats 98%
PM allele of 56 repeats = lowest number of CGG repeats reported to be
associated with a single generation expansion into a FM (Fernandez –
Carvajal et al., 2009)
45-54 CGG repeats (Intermediate) Do not transmit a FM
Expansion to a PM length in their
offspring has been described

59. Uninterrupted CGG repeats could form secondary
structures within ovarian cells- granulosa cells
These RNA structures cause binding and
sequestering of RNA binding proteins  protein
function lost  cell toxicity
AGG interruptions in repeat sequence prevent the
formation of these secondary repeat structures
lower sequestering of proteins  prevent cell
dysfunction in ovary of women carrying PM
Lekovic et al(2017) CGG repeat length and AGG interruptions as indicators of
fragile X-associated diminished ovarian reserve. Genetics in Medicine.
Most normal alleles have greater than or equal to 2 AGG
interruptions between 5 and 50 CGG repeats

60. Number of AGG interruptions
within CGG repeat region is
inversely correlated with the
instability of a PM allele and
the risk of its expansion to a
FM (Eichler et al., 1994)
Yrigollen et al. (2012) reported
that the presence of AGG
interruptions reduces the risk
of transmission of a FM,
specifically for maternal alleles
containing <100 repeats
Nolin et al. (2015) found that in
each CGG repeat size category,
those without any AGG
interruptions had the greatest
risk of instability and expansion
into a FM

61. Number of CGG repeats within maternal PM allele is in direct correlation with probability of
expanding into a FM in the offspring (Nolin et al., 2011)
Maternal allele with 55-59 CGG repeats 3.7% risk of expanding into a FM in the next
generation
≥100 repeats 98%
PM allele of 56 repeats = lowest number of CGG repeats reported to be associated with a single
generation expansion into a FM (Fernandez – Carvajal et al., 2009)
45-54 CGG repeats (Intermediate) Do not transmit a FM
Expansion to a PM length in their offspring has
been described
With at least one AGG interruption within the
allele, risk is reduced to less than 1%

62. Pattern of inheritance
Transmission to offspring and its phenotype
depends on
Sex of parent
transmitting
gene
Sex
of
child
Number of
CGG repeats
within the
parental
FMR1 gene
Stability of affected allele, which
depends on presence of AGG
trinucleotide interruptions
within the allele
PM female are at risk of FXDOR/FXPOI regardless of sex of parent transmitting PM
(Murray et al., 2000, Sullivan et al., 2005)

63. PRECONCEPTION COUNSELLING

64. 2 major problems can be potentially avoided by
early identification of PM
Development of
FXDOR/FXPOI before
childbearing
Presence of FM and its clinical
manifestations in offspring

65. Screening and Patient Counseling
ACOG recommends PM carrier screening for women with a family history of fragile X-related
disorders/intellectual disability, who are considering pregnancy/ are currently pregnancy
(Committee on Genetics, 2017)
Importance of testing women who present with unexplained ovarian insufficiency and/or
menopausal-range FSH levels before the age of 40
Extensive family history- developmental, neurodegenerative and reproductive disability across
multiple generations
Evaluation of carrier status of the fragile X mutation seeks to determine the number of CGG
repeats and, if in the full mutation range, to assess the methylation status
Southern blot and polymerase chain reaction (PCR) are the preferred methods of determining
the number of CGG repeats within the FMR1 gene for either screening or diagnostic purposes.

67. Conditions included in an
expanded carrier
screening panel should
meet the following
criteria
Have a carrier
frequency of one
in 100 or greater
Well-defined
phenotype
Require surgical
or medical
intervention
Cognitive or
physical
impairment
Detrimental
effect on
quality of life
An onset
early in life
(Committee on Genetics, 2017)

68. FXS
phenotype
is well
defined
FXS and the molecular
biology of FMR1 gene –
significantly more
complex than the other
single- gene screening
targets
PM-carrier state- is also
disease causing, unlike
heterozygous carrier
mutations screened for AR
diseases(CF)
Course as well as
transmission to the next
generation, can be
influenced by medical
intervention
Population-based carrier screening has
been already implemented in certain
countries that experience a higher
incidence of this disorder (Geva et al., 2000)

69. American College of Medical Genetics (ACMG) practice guidelines
Recommend testing the repeat region of FMR1 in women who are experiencing
reproductive problems associated with elevated FSH levels
a family history of premature ovarian failure
a family history of fragile X syndrome
male or female relatives with undiagnosed mental retardation

71. Variant Recommendations
Full mutation – male, female
Premutation – male
Intermediate range –
female,male
Genetic counselling and FMR1 DNA testing
recommended for at-risk family members to
determine the size of their FMR1 allele
Prenatal diagnosis in future pregnancies should be
considered
Premutation- heterozygote
female
+ determination of AGG interruptions

72. Possible clinical manifestations
pertinent to her, her future
offspring and other family
members
Likelihood of CGG
repeat expansion to
FM
Early childbearing- opportunity
to make an informed decision
regarding their reproductive
and family planning
Avoid risk factors of
POI – smoking
Hormonal
contraception may
mask POI symtoms
Child-free living 
appropriate
contraception is a
must
No further
children/adoption
Oocyte/sperm
donation from
unaffected donors
Fertility preservation
– oocyte/embryo
cryopreservation- not
in established POI
IVF with PGD
Fetal genetic testing-
CVS/Amniocentesis
Benefits of Early identification of PM

73. Interventions
Avoid smoking
Healthy lifestyle
involving weight-
bearing exercise
Maintenance of
normal body weight
Balanced diet –
recommended
intake of calcium
and vitamin D
Hormone
replacement
therapy
Emotional support

74. PREIMPLANTATION GENETIC DIAGNOSIS

75. Preimplantation Genetic Diagnosis
To achieve a pregnancy with an
unaffected embryo
Day 3 embryos- 1-2
blastomeres
Blastocyst – 4-8 cells
Limited amount
of genetic
material – 6pg
of genomic
DNA/cell
Determination
of CGG repeats
within FMR1
allele using
single cell PCR
 amplification
failure
Inability to
accurately
distinguish
between PM
and FM
LINKAGE ANALYSIS – certain
DNA sequences that are close
together on a chromosome
are less likely to be separated
during chromosomal
crossover and therefore are
inherited together
Genetic testing of the couple’s relatives
(siblings, parents, or any living children) using
either short tandem repeat (SRT) or less
commonly single nucleotide polymorphisms
(SNP) analysis, allowing an indirect
identification of the affected maternal FMR1
gene in the oocyte.

76. Preimplantation Genetic Diagnosis
FXDOR/FXPOI – less
responsive to COH
 ↓ availability of
embryos for PGD
accuracy of
PGD
98%–99%
confirmation with prenatal
testing later in pregnancy is
recommended.

77. PRENATAL DIAGNOSIS

78. CVS Amniocentesis
Placental cells Amniotic fluid with fetal cells
10-13 weeks, under US guidance 15-20 weeks
General risk of miscarriage - <1% Lower risk of miscarriage
Earlier diagnosis  earlier termination Later diagnosis
Rare chance of placental mosaicism No placental mosaicism
Methylation pattern(repeat number) in
placental tissue at 10-12 weeks is
incomplete  might not reflect that
observed in live born
Accurate and reliable regarding both
methylation status, number of repeats
Follow up amniocentesis

79. Take Home messages

81. Heterogenous phenotype
Complex
inheritance
Fragile X carrier status has
important reproductive and health
implications both for the individual
tested as well as potential risks for
developmental disability in future
offspring
Comparable to Down’s
syndrome
Early identification 
prevent ovarian failure
before childbearing + ↓FXS
prevalence
Given the high incidence of
both a PM and a FM in the
general population, this is
the time to take a step
forward and offer to screen
all women with DOR/POI