Vol. 008
Fragile X Syndrome and Infertility

Fragile X Syndrome and Infertility
Case Example - Not One, but Three【Abstract】
A case review of a female patient who was treated for infertility of unknown reasons andbecame pregnant with a set of triplets. She successfully gave birth to a son and two daughters.
During pediatric years, all three children showed developmental delays and were diagnosed with
Fragile X syndrome. The female patient then discovered that she was in fact a carrier for Fragile Xsyndrome.
Fragile X syndrome is the most common form of inherited intellectual disability. Females who arepremutation carriers of Fragile X syndrome not only have an up to 50% risks to have affected children,
they are also at increased risks for primary ovarian failure and late-onset tremor and ataxia. Therefore,
infertility issues can be a presenting clinical feature for premutation carriers.
In addition to a family history suggestive of Fragile X syndrome, guidelines from professional
medical societies also recommend women with unexplained ovarian insufficiency, or an elevatedfollicle-stimulating hormone level before 40 years of age be offered Fragile X syndrome carrier
screen. Preconception or prenatal genetic testing can identify affected embryos or fetuses prior tobirth. Many families are not aware they are at an increased risk to have a child with Fragile X
syndrome until when their child is diagnosed with the condition during childrhood. However, asimple blood test could have changed the whole story.
This newsletter also includes a recent statement put forth by the American Congress of
Obstetrician and Gynecologists regarding Fragile X carrier screen, as well as a review of this genetic
condition.

【Case Example】
Mary was seen at a fertility center due to infertilityof unknown reasons. Through the assistance of fertility
treatment, Mary became pregnant with triplets andsuccessfully gave birth to two girls and a boy.
During pediatric years, all three children were
found to have developmental issues. The boy wasnon-verbal and had severe intellectual disability. One ofthe girls had mild intellectual disability, attention deficit

GGA Corp. Genetic Counseling Newsletter – Vol. 008
Fragile X Syndrome and Infertility

2hyperactivity disorder (ADHD) and anxiety issues. The other girl had learning disability, severe
anxiety and behavioral issues. An intake of the family history revealed that Mary’s father(grandfather of the three children) had tremor problem and gait changes.
Genetic testing was performed and all three children were confirmed to have Fragile X
syndrome. Follow-up parental testing revealed Mary herself was a premutation carrier of Fragile X
syndrome.
(Case source: Asuragen)【Counseling Discussion】
1. Infertility or primary ovarian insufficiency can be a clinical presentation for Fragile X
premutation carriers.
 About 20% of female Fragile X premutation carriers have primary ovarian insufficiency (POI)(menopause before age 40 years).
2. Fragile X premutation carrier status can be determined through a simple blood test.
Premutation carriers have increased risk to have children affected with Fragile X syndrome.
 The number of CGG trinucleotide repeats on the FMR1 gene determines whether a person has
normal allele (<44 CGG repeats), intermediate allele (45-54 CGG repeats), premutation allele(55-200 CGG repeats) or full-mutation allele (>200 CGG repeats) for Fragile X syndrome.
 If Mary was offered carrier screen as part of her infertility work-up, she would have found out
prior to becoming pregnant that she is a premutation carrier and has an up to 50% risk to haveaffected children.
3. Genetic test targeted at the analysis of the FMR1 gene performed through amniocentesis
prenatally or preimplantation genetic diagnosis (PGD) preconceptionally are available tohigh-risk families. Families can know whether their children are affected and have options formaking pregnancy decisions.
 If Mary was aware of her risk to have affected children, she would be able to discuss with her
physicians the option to consider in vitro fertilization (IVF) with PGD. PGD can screen whether
the embryos inherited the abnormal FMR1 allele and allow selection of normal embryos fortransfer.
If PGD test was not elected, Fragile X syndrome testing is also available through amniocentesis
during pregnancy to determine the fetal status prior to birth.

4. In addition to primary ovarian insufficiency, both male and female premutation carriers haverisks for Fragile X-associated tremor/ataxia syndrome (FXTAS).

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Fragile X Syndrome and Infertility

3



FXTAS usually starts around 50 years of age or later. It is characterized by progressive

cerebellar ataxia and intention tremor. Cognitive function is sometimes affected as well.
Knowledge of this risk can affect medical management of the carrier himself/herself as well as
his/her families.

5. Relatives of premutation carriers are at risk to also be carriers themselves.
 Mary’s sister is also at risk to be a Fragile X premutation carrier and to have affected children,infertility issues and late-onset neurological disorders. Carrier screen can be considered for
Mary’s relatives.

【Recommendations from Professional Society】
According to ACOG’s Committee Opinion #691 – Carrier Screening for Genetic Conditions, carrier
screening for Fragile X syndrome is recommended for:

Women with a family history of Fragile X-relateddisorders who are considering pregnancy orcurrently pregnant
Women with a family history of intellectual
disability suggestive of Fragile X syndrome whoare considering pregnancy or currently pregnant
Women with unexplained ovarian insufficiency or
failure or an elevated follicle-stimulating hormone
level before age 40 years
Women who does not have a family history but
are interesting in knowing their riskThis newsletter is produced and owned by GGA Corp.
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GGA Corp. Genetic Counseling Newsletter – Vol. 008
Fragile X Syndrome and Infertility4【Fragile X Syndrome】【Clinical Features】
Affected PatientsIntellectual disability – Males: moderate; Females: mild

Characteristic appearance – large head, long face, prominent forehead and chin, protrudingearsConnective tissue findings – joint laxity

Developmental delays

Large testes after pubertyBehavioral abnormalities – tantrums, hyperactivity, autism spectrum disorderOphthalmologic (strabismus), orthopedic (joint laxity), cardiac (mitral valve prolapse), andcutaneous (excess softness and smoothness) findings

Premutation CarriersMales and females – increased risk for Fragile X-associated tremor/ataxia syndrome (FXTAS)(late-onset, progressive cerebellar ataxia and intention tremor, cognitive deficits)

Females -- increased risk of FMR1-related primary ovarian insufficiency (POI) (menopause
before age 40 years)【Treatment and Management】
Fragile X syndrome: early developmental intervention, special education, and vocational training;
individualized pharmacologic management of behavioral issues that significantly affect socialinteraction; routine treatment of medical problems
FXTAS: supportive care for gait disturbance and/or cognitive deficitsPOI: reproductive endocrine evaluation for treatment and counseling for reproductive options【Prevalence】
According to American College of Medical Genetics Practice Guidelines and the World HealthOrganization:
Fragile X syndrome: Females 1/4,000-8,000; Males 1/3,600-4,000

Premutation carriers: Females 1/259-350; Males 1/800-1,000

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Fragile X Syndrome and Infertility

5【Fragile X Syndrome】【Genetic Mechanism】
Fragile X syndrome is caused by abnormal FMR1 gene which is located at the q28 region of the X
chromosome. Mutations in the FMR1 gene lead to an abnormal methylation pattern, and in turn,result in the loss of function of the FMR1 gene and abnormal clinical features.
The number of CGG trinucleotide repeats on the FMR1 gene correlate with the disease status.
More than 99% of affected individuals have abnormally increased number of CGG trinucleotide
repeats, typically >200 CGG repeats (full mutation allele). Women who are premutation carriers
have CGG repeats between 55-200 CGG repeats and are at risk to have affected child.

【Anticipation】
The number of CGG repeats on the FMR1 gene is unstable and can increase when transmitted tothe next generation. A premutation allele is at risk to expand into a full-mutation allele during
parent-child transmission, especially if transmitted from a mother to her sons/daughters.
Expansion of the CGG repeat size is less likely to occur if transmitted from father to daughter. (Afather does not pass the X chromosome to his sons.) For instance, a mother who is a premutation
carrier with 70 CGG repeats can give birth to an affected son who has 300 CGG repeats (fullmutation allele).

【Inheritance Pattern】
X-linked dominant【Genetic Testing】
Determination of CGG repeat size andmethylation status
can be done by molecular genetic tests, such as PCR andSouthern blot. Atypical genetic changes in the FMR1 genecan be evaluated with other techniques such as sequencing

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Fragile X Syndrome and Infertility

6【Fragile X Syndrome】or deletion/duplication analysis.

【Genetic Counseling】
Preconception
1.

Women with a family history, infertility due to POI or elevated FSH, or simply worried about
her risk to have affected children can consider carrier screen for Fragile X syndrome.

2.

Female premutation carriers can have an up to 50% risk to have an affected child. In vitro
fertilization with preimplantation genetic diagnosis (IVF with PGD) for Fragile X syndrome isan option for high-risk families to know the disease status of embryos and help withselection for transfer/implantation.

Prenatal
1.

Fetuses affected with Fragile X syndrome usually do not show abnormalities on prenatal
ultrasound scans.

2.

Pregnant women who are Fragile X premutation carriers can consider fetal FMR1 genetic
testing through amniocentesis to confirm the disease status of the fetus.

3.

If a fetus is found to be affected, prenatal prediction of the severity of postnatal clinicalpresentation is not possible. Couples whose fetuses are confirmed to have Fragile X
syndrome are recommended to have genetic counseling and would need to make pregnancy
decisions based on personal acceptance levels and situations.

Postnatal
1.

About 1-5% of children with autism spectrum disorder have Fragile X syndrome. The number
could be as high as 25% for children with autism spectrum disorder and intellectual
disability.

2.

Individuals showing features and symptoms suspicious of Fragile X syndrome can benefit
from molecular genetic testing to rule-in/rule-out a Fragile X syndrome diagnosis.

3.

If Fragile X syndrome is confirmed, care and management from multi-disciplinary specialties
can assist the patient in achieving his/her greatest potential.

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GGA Corp. Genetic Counseling Newsletter – Vol. 008
Fragile X Syndrome and Infertility

7【Fragile X Syndrome】【Extended Reading】
 GeneReviews – FMR1-related Disorder
https://www.ncbi.nlm.nih.gov/books/NBK1384/
 Genetics Home Reference – Fragile X syndrome
https://ghr.nlm.nih.gov/condition/fragile-x-syndrome National Fragile X Foundation
https://fragilex.org/

Reference:
1.
2.
3.
4.
5.

American Congress of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 691:
Carrier Screening for Genetic Conditions. Obstet Gynecol. 2017 Mar;129(3):e41-e55.
Fragile X syndrome case source: Anderson A, Scientific Affairs Manager, Genetics, Asuragen, personalcommunication, July 2016.
World Health Organization: Genes and Human Disease [Internet][cited 2017 July 5]. Available from:http://www.who.int/genomics/public/geneticdiseases/en/index2.html.
Sherman S, Pletcher BA, and Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005
Oct;7(8):584-7.
Schaefer GB, Mendelsohn NJ; Professional Practice and Guidelines Committee. Clinical genetics evaluation inidentifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013
May;15(5):399-407.

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