Prenatal & Preconception Carrier Screening for Fragile X: Clinical and Genetic Essentials

WHAT IS IT?

Fragile X is a serious X-linked dominant genetic disorder that is strongly associated with significant developmental and CNS manifestations. Prevalence approximately 1/4000 males and 1/8000 females.

When to Offer Prenatal/Preconception Screening for Fragile X?

ACOG

ACOG does not recommend universal screening for this disorder but rather the test should be offered based on clinical context
Fragile X screening is indicated for the following
- Family or personal history of unexplained autism, intellectual disability or fragile X related disorders (see below)
  - Family history: obtain a 3 generation pedigree and pay particular attention to male relatives
- Unexplained ovarian insufficiency or failure
- Elevated follicle-stimulating hormone (FSH) level before age 40 years
- If patient does not meet above criteria but requests screening
  - May offer following informed consent

ACMG

ACMG does recommend universal screening for Fragile X as part of it’s recommended ‘tier 3 panel’ (see, ‘Related ObG Topics Below) that includes
- 97 autosomal recessive genes
- 16 X-linked genes, including DMD and Fragile X

Note: Genetic Counseling and informed consent are key components of screening and diagnostic testing

KEY CLINICAL FINDINGS:

NEUROLOGIC
- Intellectual disability
  - Males: Mild to moderate
  - Females: Seen in approximately 1/3
- Features of autism spectrum disorder (approximately 1/3)
- Attention Deficit Disorder (ADD)
- Anxiety and hyperactive behaviors
- Language delay
- Seizures
  - Males: 15%
  - Females: 5%
HEAD AND NECK
- Macrocephaly
- Coarse facies
- Large forehead
- Prominent jaw
CARDIOVASCULAR
- Mitral valve prolapse
CHEST
- Pectus excavatum
GENITOURINARY
- External Genitalia (Male)
- Macroorchidism

KEY POINTS:

Genetics

Most cases (98%) caused by expanded trinucleotide repeat (CGG)n in the FMR1 gene

Unaffected: < 45 repeats
Intermediate: 45-54 repeats
- Approximately 14% of intermediate alleles are unstable and may expand into the premutation range when transmitted by the mother
- Does not incur risk to offspring for fragile X
Premutation: 55 to 200 repeats
- Some boys with premutations show milder features, including large ears, autistic features, anxiety or depression
- Females are at increased risk for fragile X-associated primary ovarian insufficiency (FXPOI)
  - May be overt with premature ovarian failure (POF) before age 40 or occult (reduced fertility)
  - 1/200 women have premutation but only 25% will be affected
- Primarily males are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS)
  - Movement disorder (intention tremor and ataxia) that also affects cognition
  - Late-onset progressive disorder > 50 years, and its signs and symptoms worsen with age
  - 1/450 males have premutation but only 40% will be affected
  - 1/200 females have the premutation but only 16% will be affected
Symptomatic: > 200 repeats due to silencing (methylation) of the FMR1 gene located on the X chromosome

Complexity Related to Inheritance Pattern

Females: premutation can expand to > 200 CGG repeats during oogenesis
Males: premutation does not expand during spermatogenesis
- Men pass the premutation only to daughters

Premutation Expansion Risk Based on Number of Repeats

More CGG repeats increase the risk of full mutation expansion to fragile X (>200 repeats)
AGG ‘interruptions’
- Located in the FMR1 repeat regions
- Most individuals have 1 or 2 AGG interruptions
- AGG interruptions stabilize FMR1 to prevent premutation expansion
  - More AGGs, decreased risk to full expansion
- Being used by some clinical laboratories to refine fragile X risk to offspring in maternal permutation carriers
  - >90 repeats very high risk and >90% will expand to full mutation regardless of AGG

Maternal Repeat Size	%Full Mutation	#AGG – %Full Mutation
45 – 49	0%	0%
50 – 54	0	0%
55 – 59	0.5	0 AGG – 3% >1 AGG – 0%
60 – 64	1.7	0 AGG – 5% >1 AGG – 0%
65 – 69	7	0 AGG – 17% >1 AGG – 0%
70 – 74	21	0 AGG – 52% 1 AGG – 7% 2 AGG – 0%
75 – 79	47	0 AGG – 73% 1 AGG – 33% 2 AGG – 7%
80-84	62	0 AGG – 87% 1 AGG – 67% 2 AGG – 15%
85 – 89	81	0 AGG – 88% 1 AGG – 83% 2 AGG – 50%
90 – 99	94
≥100 – 200	98
>200	100

Adapted from Nolin et al., 2011 and 2015

Learn More – Primary Sources:

Fragile X analysis of 1112 prenatal samples from 1991 to 2010

Fragile X full mutation expansions are inhibited by one or more AGG interruptions in premutation carriers

GeneReviews: FMR1-Related Disorders

ACOG Committee Opinion 691: Carrier Screening for Genetic Conditions

ACMG: Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics

GHR: Fragile X Syndrome

Joint SOGC–CCMG Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to-Consumer Testing

Locate a genetic counselor or genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Locate a Maternal Fetal Medicine Specialist

Maternal Fetal Medicine Specialist Locator-SMFM