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