Prevalence and instability of fragile X alleles: implications for offering fragile X prenatal diagnosis

Obstet Gynecol. 2008 Mar;111(3):596-601. doi: 10.1097/AOG.0b013e318163be0b.


Objective: To document fragile X allele frequencies in a national referral population and evaluate CGG repeat expansion in mother-offspring transmissions.

Methods: Fragile X DNA analysis by Southern blot and polymerase chain reaction was completed for 14,675 women, aged 18 years or older, and 238 mother-offspring pairs between January 1999 and June 2004. Carrier frequencies were compared between groups referred for different clinical indications. Direct comparison of the FMR1 gene CGG repeat size in mother-offspring pairs determined intermediate and premutation allele stability.

Results: Intermediate fragile X alleles (45-54 CGG repeats) occurred in 257 (1 in 57). The combined total number of patients with a premutation (55-200 CGG repeats) or full mutation (more than 200 CGG repeats) numbered 208 (1 in 71). One in 3.5 women with a family history of fragile X and 1 in 10 with premature ovarian failure had a FMR1 mutation. This compared with 1 in 86 for those with a family history of mental retardation and 1 in 257 for women with no known risk factors for fragile X. Among 238 mother-offspring pairings, the smallest allele to expand to a full mutation in one generation contained 60 CGG repeats. Although 6.6% (4 of 60) of intermediate repeat alleles did expand, none jumped to a clinically significant full mutation-sized allele.

Conclusion: Based on these data and other published literature, offering invasive prenatal diagnosis for fragile X syndrome is not indicated for women with intermediate alleles. Invasive prenatal diagnosis is warranted for those women with a fragile X allele containing 55 or more CGG repeats.

MeSH terms

  • Adolescent
  • Adult
  • Female
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / epidemiology
  • Fragile X Syndrome / genetics*
  • Genes, X-Linked / genetics
  • Genetic Carrier Screening
  • Genetic Counseling*
  • Genetic Testing
  • Humans
  • Infant, Newborn
  • Pregnancy
  • Prenatal Diagnosis / methods*
  • Prevalence
  • Trinucleotide Repeat Expansion / genetics*
  • United States / epidemiology


  • FMR1 protein, human
  • Fragile X Mental Retardation Protein